WO2004013324A1 - Novel crystalline tryptase and utilization thereof - Google Patents

Novel crystalline tryptase and utilization thereof Download PDF

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Publication number
WO2004013324A1
WO2004013324A1 PCT/JP2003/009738 JP0309738W WO2004013324A1 WO 2004013324 A1 WO2004013324 A1 WO 2004013324A1 JP 0309738 W JP0309738 W JP 0309738W WO 2004013324 A1 WO2004013324 A1 WO 2004013324A1
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compound
tryptase
activity
pharmacophore
woiv
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PCT/JP2003/009738
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French (fr)
Japanese (ja)
Inventor
Tomokazu Matsusue
Yutaka Miyazaki
Ikuya Shiromizu
Tadashi Manabe
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Mochida Pharmaceutical Co., Ltd.
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Priority to AU2003252355A priority Critical patent/AU2003252355A1/en
Publication of WO2004013324A1 publication Critical patent/WO2004013324A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes

Definitions

  • the present invention relates to a trypase having activity obtained by cleaving a sugar chain, a method for producing the same, a method for producing a crystallized trypase using the tryptase, the trypase and a specific trypase.
  • the present invention relates to a complex crystal with a compound that inhibits zein activity.
  • the present invention relates to a screening method or a drag design method using the method, and a library obtained by the drag design method.
  • Tryptase (enzyme number 3.4.2.59) is a proteolytic enzyme belonging to serine proteinase, like trypsin, thrombin, factor Xa (FXa), and kallikrein.
  • ⁇ 1, II, ⁇ I, II, III, (I, II, 5I, ⁇ , etc. tryptase cDNAs have been obtained.
  • ⁇ -tryptase and trypticase are mast cells and basophils.
  • a Tryptase and; 3 tryptase have 93% amino acid sequence homology, whereas a tryptase is constantly secreted from mast cells.
  • Human 3 trypsinase has been cloned by Niles, Maftit et al. (Biotechnol. Appl. Biochem. 28, 125, 1998), and recombinant human iS tryptase has been obtained.
  • the obtained recombinant human 3 trypase has a molecular weight of 33 kDa to 50 kDa and is heterogeneous.
  • the document states that the core protein becomes 33 kDa when treated with PNGaseF or EndoH after heat denaturation of tryptase.
  • a similar description is also given in WO 99/60139 by the same inventors, but there is no description of the conditions for cutting the sugar chain of trypsinase.
  • Tryptase has also been suggested to be associated with disease states. For example, in patients with systemic anaphylactic shock, such as bee algi, the blood iS-triplease content is continuously elevated (Schwartz et al., New, England, Journal, Ob, Medicine (N Engl. J. Med.), Vol. 316, pp. 1622-1626, 1987). In addition, allergen inhalation in patients with atopic asthma increases the level of iS-trypase in the alveolar lavage fluid (Bou s Q iet et al., Journals, ovs, allergies, and cliches). Nikaru, Immunology (J. Allergy Clin. Immu no 1.), Vol. 88, pp. 649-660, 1991). There have been many reports of enhanced expression.
  • Proteinaseacti va ted recep tor-2 (PAR-2: proteinase-activated receptor-1), complement C3, VIP (Va soacti ve intestinal peptide: vasoactive intestinal peptide) ), CGRP (calcit on in gene—related peti de: calcitonin gene-related peptide), etc., have been reported, and through these protein cleavage actions, airway constriction, vascular hyperpermeability, airway epithelial cells and fibroblasts have been reported. It has been suggested that they cause activation.
  • / 3 tryptase is secreted extracellularly in the degranulation reaction, and is an inhibitor in vivo in the intracellular granule, and is co-localized with the basic protein tribus sutin ( Katsunuma et al., Biochemistry, Vol. 62, pp. 18-31, 1990) Therefore, 0 tryptase specifically causes airway contraction and airway inflammation by mast cell degranulation, and unless mast cells are degranulated. It does not seem to act on living organisms. From the above, it is considered that a substance that inhibits human / 3 tryptase is useful for treating mast cell-related diseases, particularly allergic diseases such as bronchial asthma.
  • Bode et al. (Natour, 392, 306, 1998, W099Z 40073) analyzed the crystal structure of human / 3 tryptic enzyme. Analysis of the complex crystal with APPA shows the three-dimensional structure of the tetramer of human jS tryptase, and the location of the S1 pocket near the active site, similar to trypsin, from the three-dimensional structure. ing. The vicinity of the active site of human 3-tryptase is similar to trypsin-type serine proteases (trypsin, FXa, thrombin, plasmin, etc.), which can inhibit serine proteases that exert other pharmacological effects in vivo High. A drug which does not have such a drawback and has selectivity for human 3) trypsinase is desired.
  • Bode et al. Have proposed a bifunctional inhibitor as an inhibitor of human i3 trypase by analyzing the above three-dimensional structure. However, it is a fairly high molecular weight compound because it is aimed at inhibitors that can interact simultaneously with two of the four S1 pockets of the tryptase tetramer.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have been found to have tryptase having activity and good crystallinity, a method for producing the same, a method for producing crystallized trypticase earlier than before, and tryptase.
  • a pharmacophore of a compound that inhibits human) 3-trippase activity was found.
  • a method for screening a compound inhibiting human / 3-tripse activity using the pharmacophore, a method for designing a drug, and a method for designing a compound inhibiting human 3-tripse activity obtained by the drug designing method are disclosed.
  • a library was created to solve the aforementioned problems.
  • the present invention provides the following novel trypase, its production method, crystallization Provided are a method for producing trypticase, a complex crystal, a screening method, a drug design method, a library, and a pharmacophore.
  • a method for producing trypticase a complex crystal
  • a screening method a screening method
  • a drug design method a drug design method
  • a library a library
  • a pharmacophore pharmacophore
  • Tryptic (1) which can be crystallized within 2 months by sitting drop vapor diffusion method.
  • the treatment with the sugar chain-cleaving enzyme is carried out in the presence of a chelating agent at a temperature of 30 to 40 ° C in a buffer of ⁇ 5.0 to ⁇ 7.0. (6).
  • a method for producing a tryptase crystal comprising treating native tryptase or recombinant tryptase in a native state with a sugar chain-cleaving enzyme to crystallize the same.
  • a method for screening for a compound that inhibits tryptase activity comprising:
  • the step of virtually selecting the compound that inhibits the tryptase activity in the step (ii) is performed by applying the pharmacophore to computer software to virtually convert the compound that inhibits the tryptase activity that satisfies the pharmacophore.
  • the screening method according to (15), which is a step of selecting is performed by applying the pharmacophore to computer software to virtually convert the compound that inhibits the tryptase activity that satisfies the pharmacophore.
  • a method for screening a compound that selectively inhibits human / 3 tryptase activity comprising:
  • a pharmacophore that satisfies all of the conditions 1 to 4 described in Table 2 described below is supplied to computer software, so that the pharmacophore is A method for screening a compound that selectively inhibits human / 3 tryptase activity, comprising a step of virtually selecting a compound that inhibits human 0 tryptase activity.
  • a drug design method for a compound that selectively inhibits human / 3 tryptase activity comprising the following steps:
  • a drug design method for a compound that selectively inhibits human 0-trypticase activity comprising the following steps:
  • (22) Human] 3 is a method for preparing a compound array consisting of compounds capable of selectively inhibiting trypsinase activity, wherein the pharmacophore described in Table 1 below is prepared. A human who satisfies the pharmacophore by applying it to a computer software; 6 A method of virtually selecting a compound that selectively inhibits tryptase activity, preparing the selected compounds in real time, and combining them to form a compound array .
  • FIG. 1 is a diagram of a sugar chain cleavage site of a sugar chain cleavage enzyme (enzyme belonging to the enzyme number 3.2.1.96) Endo- ⁇ - ⁇ —acetylglgucosamidnidase.
  • FIG. 2 is a flowchart showing an example of the screening of the present invention.
  • FIG. 3 shows the results of electrophoresis by SDS-PAGE of the purification process of trypsinase with sugar chains cleaved.
  • FIG. 4 is a Ripon diagram of a complex of a human] 3 trypase tetramer and four molecules of compound A, which was convinced by three-dimensional structural analysis as a result of X-ray diffraction experiment.
  • A, B, C and D represent each molecule of tryptase.
  • FIG. 5 is a ribbon diagram of a complex of two molecules of human S-tribase and two molecules of compound A obtained from three-dimensional structural analysis as a result of an X-ray diffraction experiment.
  • FIG. 3 is a view of A and D molecules as viewed from the center of a tetramer.
  • FIG. 6 is a Ripon diagram of a complex of human
  • A, B, C and D represent each molecule of tryptase.
  • FIG. 7 is a ribbon diagram of a complex of two molecules of human tryptase and two molecules of compound A obtained from the three-dimensional structure analysis as a result of the X-ray diffraction experiment.A and D of the tryptase tetramer in FIG. 6 are shown.
  • FIG. 3 is a diagram of a molecule as viewed from the center of a tetramer.
  • FIG. 8 is a diagram showing the binding site of compound A of human / 3 tryptase, and is a diagram of the A and D molecules of the tryptase tetramer in FIG.
  • FIG. 9 is a diagram showing a binding site between human 3 tryptase and a compound A complex, and is a diagram showing the A and D molecules of the trypase tetramer in FIG.
  • FIG. 10 is a schematic diagram of the pharmacophore shown in Table 1.
  • the functional groups of the compounds are indicated by basket-shaped spheres. Shaded cells indicate adjacent tryptase molecules.
  • FIG. 11 is a diagram showing the binding site of compound B of human / 3 tryptase, and is a diagram of the trypase tetramer A and D molecules of FIG.
  • FIG. 12 is a diagram showing the binding site between the human
  • FIG. 13 is a schematic diagram of the pharmacophore shown in Table 2. The functional groups of the compounds are indicated by basket-shaped spheres. The compound and the tryptase molecule represent two molecules each.
  • FIG. 14 is a schematic diagram of the characteristic sphere used in Example 7 (2) -11.
  • A is a diagram in which compound A is described as a base.
  • B is a diagram showing the distance between the centers of the characteristic spheres.
  • C is a diagram showing angles obtained when lines between the centers of the characteristic spheres are connected.
  • FIG. 15 is a schematic diagram of the characteristic sphere used in Example 7 (2) -12.
  • A is a diagram based on Compound B.
  • B is a diagram showing the distance between the centers of the characteristic spheres.
  • C is a diagram showing angles obtained when lines between the centers of the characteristic spheres are connected.
  • FIG. 16 is a schematic diagram of the characteristic sphere used in Example 7 (2) _3.
  • A is a diagram based on Compound B.
  • B is a diagram showing the distance between the centers of the characteristic spheres.
  • C is a diagram showing angles obtained when lines between the centers of the characteristic spheres are connected.
  • a first aspect of the present invention is a tryptase that is substantially free of sugar chains, substantially uniform, and maintains tryptase activity.
  • SDS-PAGE can be used to detect native trypsinase or recombinant tryptase by cleaving the sugar chain in a native state, and can be detected as a single band by Coomassie staining. It is ze.
  • Native refers to a state in which the three-dimensional structure of tryptase is maintained in a living body and the enzyme activity is maintained.
  • heating, strong hydrochloric acid solution, strong alkaline solution, sodium um dod e cylsulfate (SDS), urea, guanidine hydrochloride and other protein denaturants, 2-mercaptoethanol (2-ME) and D Tryptase treated with a reducing agent such as ithiothreitol (DTT) is not said to be in its native state.
  • "treating the sugar chain without denaturing” means heating, strong hydrochloric acid solution, strong alkaline solution, protein denaturant such as SDS, urea, guanidine hydrochloride, etc. This refers to the treatment of cutting the sugar chain without performing treatment with a reducing agent. Preferably, it refers to treating a sugar chain only by the action of a sugar chain cleavage enzyme.
  • the tryptase of the present invention is a tryptase which is obtained by subjecting a natural tryptase or a recombinant tryptase to a sugar chain cleavage treatment in a native state, and which can be detected as a single band by Coomassie staining on SDS-PAGE,
  • pre-treatment tryptase There is no particular limitation on the type of trypsinase to be subjected to sugar chain cleavage.
  • tryptase of molecular species such as ⁇ , ⁇ , and ⁇ .
  • trypsinase forms a tetramer under physiological conditions and expresses its activity, but a, ' ⁇ is not considered to form a tetramer.
  • r-tryptase is also called trans-me trypase (TMT), which has a hydrophobic region at the C-terminal part of the peptide, which is thought to be embedded in the cell membrane. Since there are one or two ⁇ glycoside binding sites in all ⁇ , ⁇ ⁇ , and ⁇ molecular species, trypsinase made with these natural tryptases or recombinants has sugar chains added. are doing.
  • the tryptase before treatment includes any of these tryptases.
  • tryptase is present in the lung, skin, gastrointestinal tract, eyeball, nose, etc. Any trypase can be used as a pre-treatment trypase.
  • the method of Smith et al. From trypsinase present in the lung The Journal of Biochemical Chemistry vol. 259)
  • a tryptase obtained by purification may be used as a pre-treatment tryptase.
  • trypsinase has been found in animals other than humans, and it is present in animals such as dogs, mice, rats, gerbils, guinea pigs, horsetails, and bush. Ze is also available.
  • guinea pig tryptase may be collected from the lung, and partially purified or purified tryptase may be used as pre-treatment tryptase.
  • Recombinant tryptase can be produced by a method such as HedyChan (ProteinExpression and PurificationVol. 15 251-257 (1999)).
  • a commercially available recombinant human iS tributase Promega, rh-iS I-tributase may be used.
  • it is human tryptase. More preferably, it is human / 3 trypsinase. Also preferred is recombinant trypase. Particularly preferred is recombinant human i3 tryptase.
  • the "sugar chain cleavage treatment" for obtaining the trypticase of the present invention includes "a trypticase which is detected as a single band by Kumashii staining on SDS-PAGE".
  • a sugar chain cleavage treatment using a sugar chain cleavage enzyme described below may be used without denaturing the natural tryptic enzyme or recombinant tryptase.
  • an enzyme belonging to the enzyme number 3.2.1.96, Endo— / 3—N-acetylgluccosaminidinase can be used.
  • Endo F1, Endo F2, Endo D, and Endo H are included.
  • FIG. 1 is a diagram showing the sugar chain cleavage site.
  • the sugar chain cleavage site is cleaved by Endo-iS-N-accety1g1ucosaminamidase. Because pre-treatment tryptase has an N-acetyl-chitobiose bond of a high-mannose or hybrid-type sugar chain, the sugar chain can be reduced by treatment with Endo-1] 3-N-acetylglucose ami nidase. Trypsinase can be obtained which can be cleaved and detected as a single band by Coomassie staining on SDS-PAGE.
  • sugar chain cleavage treatment refers to the above cleavage.
  • substantially the sugar chain is cut or “substantially no sugar chain” means that the asparagine residue
  • Conditions for treating the pre-treated tryptase with the sugar chain-cleaving enzyme to obtain the tryptase of the present invention are not particularly limited.
  • the condition is pH 5.0-7.0. More preferably, the condition is pH 5.0-6.0.
  • the temperature is preferably from 25 ° C to 50 ° C. More preferably, the temperature is 30 ° C. to 40 ° (:, particularly preferably 37 ° C. It is preferable to carry out the reaction near the optimum conditions of the sugar chain-cleaving enzyme using other conditions (Agric Biol Che 1990 Jan; 54 (l): 97-106).
  • the reaction of the present invention can be carried out for more than an hour to obtain the present protease.
  • the reaction may be performed in 24 hours or more.
  • Suitable chelating agents include, for example, 2 mM EDTA.
  • the tryptase of the present invention thus obtained can be purified using a conventional purification method such as a gel filtration column, an ion exchange column, a heparin agarose column, and an HP LC. Further, the concentration can be carried out by using a usual concentration method such as ultrafiltration or column concentration.
  • the tryptase of the present invention is detected as a single band by coomassie staining on SDS-PAGE. This is because tryptase before sugar chain cleavage is subjected to sugar chain cleavage treatment, This is because it becomes a trypsinase having substantially no sugar chains and is substantially uniform.
  • human 13 tryptase is used as the pre-treatment trypase, the molecular weight is detected as about 33 kDa by SDS-PAGE.
  • the tryptase of the present invention maintains the tryptase activity before the sugar chain cleavage treatment.
  • the intensity of the enzyme activity may be different from that of the pre-treatment tryptase.
  • the enzymatic activity that is, the specific activity, differs depending on the degree of purification of tryptase after sugar chain cleavage and the degree of purification of tryptase before treatment.
  • it is a tryptase in which the enzyme activity is maintained at 50% or more as compared with the tryptase before the treatment. It is more preferably 70% or more, and still more preferably 80% or more.
  • the enzyme activity may be more than 100% as compared with the tryptase before the treatment, and is preferable.
  • the method for measuring the activity of tributase is not particularly limited.
  • the method of Schwa rtz et al. (The Journal of Biochemical Chemistry 256, 11939), and the method of Smith et al. (The Journal of Biochemical Chemistry 259 vol. 1) 1046, 1984), Combining et al.'S method (Journal of Medica 1 Chemistry 41, 4854, 1998), Katz et al.'S method (Nature 391, 608, 1998), Cau ghy et al. , The method of The Journal of Immunology, The Journal of Immunology, 6217 (1997), and the method of Waills et al. (P. 264, 676). Is mentioned.
  • 1 U 100,00 OUZmg or more is preferable when defined as "the amount of trypase that increases the ⁇ fluorescence count by 1,000,000 in 60 minutes". More preferably, the tryptase is 140, OO OU / mg or more, and even more preferably, 160,00 OUZ mg or more. Further, the activity may be higher than the specific activity of the pre-treatment tryptase, which is preferable.
  • the tryptase of the present invention maintains the sensitivity to the tryptase inhibitor similarly to the pre-treatment tryptase. Therefore, it can be used for studying the binding mode of a tryptase inhibitor, ie, a tryptic enzyme ligand.
  • the IC 50 for the tryptase inhibitor of the present invention relative to the tryptase inhibitor of the present invention is preferably in the range of 10 to 1000% as compared to the IC 50 for the tryptase inhibitor for tryptase before treatment. More preferably, it is in the range of 30% to 300%.
  • the tryptase inhibitors are Antipain, Leupeptin, Leech—de ri ved Trifta ”zi nh ibitor, diis op rop y 1 fl uoropho s pha te (.The Jou rna lof Biol og ical Chemi st ry 259 11045, 1984 Hopz e-Seyler 373, 1025, 1992), 4-ami di nopheney lpyruvicacid (Nature 392, 306, 1998), and the like.
  • the trypticase of the present invention is substantially free of sugar chains and is substantially uniform, so that it can be subjected to a conventional vapor diffusion method (A. Ducruix and R. Giege: Crystallization of nucleic Acids and Proteins. A Practical Approach). , IRL PRESS at Oxford University Press (1991) p.l30), which can be achieved much faster than conventional tryptase crystals.
  • a conventional vapor diffusion method A. Ducruix and R. Giege: Crystallization of nucleic Acids and Proteins. A Practical Approach). , IRL PRESS at Oxford University Press (1991) p.l30
  • crystallization period varies somewhat, crystals can be formed within two months using a common precipitant.
  • Typical precipitants include, for example, inorganic salts represented by sodium chloride and ammonium sulfate, polyols represented by polyethylene glycol of various molecular weights, alkyl ethers thereof, and organic solvents.
  • a vapor diffusion method using polyethylene glycol which is a polyol the period for forming crystals can be further shortened.
  • the tryptase of the present invention uses 30 w / "v% polyethylene glycol 4000 as a precipitant, and further contains 0.2 mol / L ammonium acetate and 0.1 mol / L acetate buffer (pH 5.0).
  • a second aspect of the present invention is a method for obtaining a tryptase in which a sugar chain is substantially cleaved while maintaining the enzyme activity of the tryptase before the treatment.
  • the method comprises a step of treating a natural tryptase or a recombinant tryptase in a native state with a sugar chain-cleaving enzyme. This method is for producing trypsinase in which the sugar chain is substantially cleaved, which is maintained at not less than 30%.
  • the method for obtaining the tryptase of the present invention is characterized by comprising a step of treating the tryptase in a native state with a sugar chain-cleaving enzyme.
  • a third aspect of the present invention is a method for producing a tryptase crystal, comprising pretreating a natural tryptase or a recombinant trypase with the method of the second aspect of the present invention and crystallizing the same.
  • the method comprises the step of pretreating native trypsinase or recombinant tryptase with a sugar chain-cleaving enzyme in an undenatured state, and crystallizing the tryptase crystal, characterized in that it is crystallized. It is a manufacturing method.
  • a complex of the trypticase and a substance having an affinity is prepared and crystallized. And producing a complex crystal of tryptase and a substance having affinity with tryptase. Specifically, after pre-treating natural tryptase or recombinant trypase in a native state with a glycolytic enzyme, a complex of trypase and a substance having affinity is prepared. A method for producing a composite crystal of a tryptase characterized by crystallization, and a substance having tryptase and an affinity.
  • the method for producing a tryptase crystal or a complex crystal of a tryptase and a substance having an affinity with a tryptase comprises the steps of:
  • the method includes a step of performing a chain scission treatment, and a step of crystallizing tryptase or a complex of tryptase and a substance having affinity with tryptase.
  • the step of sugar chain cleavage treatment is as described in the method of the second aspect of the present invention.
  • the method for producing a crystal according to the present invention is characterized in that the method according to the second aspect of the present invention is included as a pretreatment, and using the pretreated tryptase, the tryptase, or the tryptase,
  • the step of crystallizing the complex of the tryptase and the substance having affinity is not limited and may be any step.
  • Protein crystallization can be performed using the stationary batch method, free interface diffusion method, dialysis method or vapor diffusion method (A. Ducruix and R. Giege: Crystallization of nucleic Acids and Proteins.A Practical Approach, IRL PRESS at Oxford University Press (1991) p.121-146).
  • a single crystal is precipitated by gradually lowering the solubility of the protein in the protein solution using a precipitant.
  • the single crystal described in the present specification refers to a crystal grown from one crystal nucleus precipitated due to a decrease in solubility of a protein caused in the course of crystallization using the above-described crystallization method.
  • a single crystal is required for three-dimensional structural analysis of proteins, and cannot be analyzed with a polycrystal consisting of crystals grown from multiple nuclei.
  • the crystallization step in the production method of the present invention may use any of these methods, and is not limited thereto.
  • it is a step using a vapor diffusion method.
  • Vapor diffusion methods include hanging drop, sitting drop, and sandwich drop vapor diffusion, depending on the placement of the protein-containing drop in a large excess of the reservoir solution containing the precipitant. Both methods use the vapor diffusion between the reservoir solution and the reservoir in a closed container to increase the concentration of the precipitant in the reservoir and increase the protein solubility. This is the principle that lowering the concentration promotes the precipitation of single crystals. More preferably, a high-quality single crystal can be obtained by using the sitting drop vapor diffusion method.
  • a place one level higher than the large excess reservoir solution containing the precipitant contained in a closed container is created on a table or the like placed in the solution, and a drop, which is a solution of the protein to be crystallized, is placed here.
  • a drop which is a solution of the protein to be crystallized
  • Drops are prepared with tryptase, low concentrations of precipitants and buffer solutions.
  • the reservoir solution is adjusted with a high concentration of precipitant and buffer solution.
  • Inorganic salts and polyols can be used as precipitants.
  • ammonium sulfate can be used for the inorganic salt
  • polyethylene dalicol can be used for the polyol.
  • polyethylene daricol having an average molecular weight of 150 to 800.
  • the reservoir solution preferably contains an appropriate inorganic salt in order to increase the ionic strength together with the precipitant and buffer unnecessary interactions between proteins.
  • Preferred inorganic salts include ammonium acetate, lithium chloride, magnesium chloride, calcium chloride, potassium chloride, ammonium chloride, calcium acetate, potassium acetate, and vinegar.
  • the pH is preferably weakly acidic to around neutral. The pH is more preferably from 4.5 to 5.5, and particularly preferably around pH 5.0.
  • the drop contains tryptase in a concentration of 1 to 1 Omg / mL. More preferably, it is concentrated to 1 to 5 mgZmL, and still more preferably to 2 to 3 mg / mL. Further, it is preferable that a low concentration of, for example, a precipitant, an inorganic salt or the like is added to the reservoir solution for the drop. More preferably, it is added at a concentration of 1 Z 2 of the reservoir solution. Further, it is preferable to use an additive having amino groups at both terminals of the alkyl chain. More preferably, the additive is such that the alkyl chain has a length on the order of pen. The addition concentration is preferably 0.1 to 2 Owt%.
  • the crystallization step makes the temperature uniform.
  • the preferred crystallization temperature is 4 ° C to 30 ° C, more preferably 10 to 25 ° C, and even more preferably 20 ° C.
  • the method for producing a crystal of the present invention is not limited to the method for producing a crystal consisting of tryptase alone, but includes a method for producing a complex crystal of tryptase and a substance having affinity with tryptase.
  • the method for producing a composite crystal includes a step of binding trypsinase to the substance.
  • the substance having affinity with trypsinase include compounds that inhibit tryptase activity.
  • the order of this step and the step of crystallizing is not particularly limited. Before joining It may be performed between the step of performing the treatment and the step of crystallizing. Crystallization of the composite by this production method is generally called a co-crystallization method.
  • the interaction between tryptase molecules in the crystal is performed at a position distant from the vicinity of the active center of trypase, A substance having a molecular weight that can pass through the flow path of the solvent existing in the crystal can reach the active center of the tryptase molecule constituting the crystal from the outside of the crystal without breaking the crystal. Therefore, when a substance having affinity with tryptase can pass through a solvent channel in the crystal, a soaking method is also possible in the case of producing a composite crystal of tryptase.
  • the soaking method is a method in which, after the step of crystallizing the pretreated trypase, a step of combining the tryptase with a substance having affinity with tryptase is performed.
  • a trypticase that has already crystallized as a complex of a tryptase and a substance having an affinity, a substance having an affinity different from the substance having the affinity, May be combined. This is effective when the binding form between tryptase already crystallized in a complex with another substance and the other substance is a non-covalent bond.
  • it is a step of bonding a crystal consisting only of tryptase with a substance having the affinity.
  • the step of binding tryptase with a substance having affinity with trypase is a step of adding the substance to a solution containing pretreated tryptase.
  • concentrations of trypsinase are those described above.
  • the concentration of the substance to be added is preferably equal to or higher than the molar concentration of tryptase contained in the solution. More preferably at least 5 times the molar concentration, more preferably More than 50 times molar concentration.
  • the step of crystallizing the pretreated trypsinase is as described above.
  • the step of crystallizing the pretreated trypsinase is as described above.
  • the soaking method requires a solution in which crystals can exist stably, and this is called an artificial mother liquor.
  • an artificial mother liquor a solution obtained by adding 0.85 to 1.7 mol / L NaCl to the reservoir solution described above can be used.
  • a solution to which 1.0 mol / L NaCl is added is used.
  • a substance having affinity for trypsinase is dissolved in a concentration 10 times or more higher than the Kd value of the substance for tryptase.
  • This solution is used as a soaking solution.
  • the substance is dissolved at a concentration of at least 100 times, more preferably at least 1000 times, the Kd value.
  • Complex crystallization is performed by immersing trypsinase crystals in a soaking solution.
  • the soaking temperature should be uniform.
  • the temperature is preferably 4 ° C to 30 ° C, more preferably 10 to 25 ° C, and still more preferably 20 ° C. Under the above conditions, a complex crystal of tripse and the substance can be produced with the immersion time usually within 12 hours to 4 days.
  • the crystal of tryptase obtained by the production method of the present invention or a complex crystal of tryptase and a substance having affinity with tryptase inhibits a novel trypase activity by being used for crystal structure analysis. It can contribute to compound drug discovery.
  • a fourth aspect of the present invention is a complex crystal of the tryptase of the first aspect of the present invention and a substance having an affinity for the trypase. 2003/009738
  • the substance having an affinity for trypsinase is preferably a compound that inhibits tryptase activity.
  • the tryptase of the first aspect of the present invention is as described in the first aspect of the present invention.
  • the method for producing the composite crystal of the present invention is as described in the third embodiment of the present invention.
  • a fifth aspect of the present invention is a complex crystal of tryptase and a compound that inhibits a specific novel tryptase activity. Specifically, it is a composite crystal of tryptase and N- [2- [N- [3- [4- (aminomethyl) phenyl] propyl] amino] ethyl] -2-naphthalenesulfonamide or a salt thereof. Tryptase and N- [2- [N- [3- [4- (aminomethyl) phenyl] propyl] -N-methylamino] ethyl] -2-benzo [b] thiophenecarboxamide or This is a composite crystal with a salt.
  • the salt is not particularly limited. At the time of production, a salt having a relatively small molecular weight is preferable in consideration of a complex with trypsinase.
  • an inorganic salt More preferably, it is a borate, a sulfate or a hydrochloride. Particularly preferred is the hydrochloride.
  • the method for producing the composite crystal is as described in the third embodiment of the present invention.
  • the three-dimensional structure coordinates of the complex can be obtained from the above-described complex crystal by performing the structural analysis described in a sixth aspect of the present invention described below.
  • By analyzing the obtained structural analysis coordinates it is possible to identify the amino acid residues at which compound A or compound B, which selectively inhibits human / 3 trypase, interacts with human 3 tryptase. is there.
  • by displaying the coordinates of the complex molecules and extracting the amino acid residues involved in the interaction by using existing molecular design software (SYBYL, Tribos, PlayStationlll, Accelrys, etc.), it is particularly important for industrial applications. It is also possible to extract various properties and information.
  • the sixth embodiment of the present invention is a novel method for screening compounds that inhibits tryptase activity, and is classified into two types.
  • the first is a method for screening for a compound that inhibits trypsinase activity, comprising the following steps.
  • the step (1) is a step of using the method for producing a crystal according to the third embodiment of the present invention to form a complex crystal of a glycosylated treptase and a compound which is known to inhibit tryptase activity in advance. is there.
  • a compound which is known to inhibit tryptase activity in advance is there.
  • the compound described in WO99 / 40073, APPA may be used.
  • a compound that is not known but has been obtained by the practitioner that the compound inhibits trypsinase activity may be used.
  • step (2) the structure of the crystal prepared in the step (1) is analyzed, and a pharmacophore of a compound that inhibits the tryptase activity is prepared from the interaction between the sugar chain-cleaved trypsinase and the compound. This is a step of selecting a compound that inhibits the activity in a virtual manner.
  • Structural analysis of the complex crystal is performed using a laboratory X-ray diffractometer or a large synchrotron radiation facility (ES RF, APS, SP rigning-8, PF, ALS, CHESS, SRS, LLNL, SSRL, Brookhaven, etc.)
  • ES RF laboratory X-ray diffractometer
  • APS large synchrotron radiation facility
  • PF PF
  • ALS CHESS
  • SRS LLNL
  • SSRL Brookhaven, etc.
  • data can be collected using a two-dimensional detector such as an imaging plate or a CCD camera, and the three-dimensional structure of the complex of tryptase and the activity modulator can be determined from the data by X-ray crystal structure analysis.
  • the diffraction intensity obtained by integrating the index of each diffraction spot and the integration can be calculated.
  • Diffraction spots amount to about 100,000 or more in the case of this tryptic crystal.
  • the inverse Fourier transform is performed using the index of the diffraction spots and the integrated intensity to derive the electron density in a three-dimensional space.In the diffraction experiment, information on the phase of each diffraction spot required for calculating the electron density is obtained. It is impossible in principle to measure.
  • the electron density it is necessary to estimate the phase, which is the information lost by the molecular replacement method, the heavy atom isomorphous replacement method, the multi-wavelength anomalous dispersion method, or a modification thereof.
  • the molecular replacement method it is preferable to use a molecular replacement method.
  • the molecular replacement method uses the 3D coordinates of the protein with a high degree of homology to the protein to be analyzed as a search model to estimate how the molecule to be analyzed is oriented in the lattice within the crystal and constitutes the crystal How to If we can estimate the structure of the pseudo crystal using the search model, we can estimate the phase information of each diffraction spot by performing a Fourier transform from it. The estimated phase information is subjected to inverse Fourier transform together with the measured diffraction spot intensity. These are all performed by software on a computer, so no experiments are required and the analysis can be performed very quickly. According to the electron density map obtained in this way, a 3D model is constructed using software running on a graphics workstation. After constructing this model, it is constructed using the least squares method, maximum likelihood method, Simulated Annealing method, etc. The structure is refined to obtain the final three-dimensional structure of the complex.
  • a pharmacophore of tryptase and the compound can be prepared.
  • a pharmacophore is a physicochemical feature on a compound that is required to bind to a target protein.
  • a pharmacophore can be defined by determining the relative distance between specific functional groups of a compound, and by expressing structural physicochemical characteristics as characteristic spheres and determining the relative distance between characteristic spheres. It is also possible to define It is also possible to define one of the structural physicochemical characteristics as one site of the pharmacophore based on the interaction with the protein and the distance from the protein, and define the pharmacophore as a set of sites.
  • the pharmacophore can be defined by any method commonly used by those skilled in the art, and is not limited to the method described above.
  • the characteristic sphere refers to a spatial region that retains various physicochemical properties such as hydrophobicity, chargeability, ability to form hydrogen bonds, and the like.
  • pharmacophore construction program Catalyst (Accelrys Inc., San Diego, CA)
  • “Hydrogen-bond Acceptor furthermore, Hydrogen-bond Acceptor lipid can be classified”
  • “Hydrogen-bond Donor” "Hydrophobic” (also classified as Hydrophobic Aromatic and Hydrophobic aliphatic)
  • Negative Charge "Negative Ionizablej”
  • Positive Charge rpositive Ionizablej
  • Factory Ring A refers to a spatial region that retains various physicochemical properties such as hydrophobicity, chargeability, ability to form hydrogen bonds, and the like.
  • the hydrophobic region, the hydrogen bond acceptor region, the cation region, the cyclic aromatic region, etc. are defined as physicochemical properties
  • the characteristic sphere is represented as a spherical region having these physicochemical properties. I can do it.
  • Examples of atoms and functional groups suitable for each characteristic sphere are defined in the manual attached to the program such as Catalyst (Accelrys Inc., Catalyst Document at ion Relax 4.5, 1999). ).
  • the pharmacophore obtained in step (1) of the screening method of the present invention when expressed as the above-mentioned characteristic sphere, is located at the protein-ligand interaction site of the compound used for the complex crystallization of tryptase and tryptase. It is represented by a matching characteristic sphere or set of characteristic spheres.
  • the step of virtually selecting a compound that inhibits trypsinase activity from the pharmacophore prepared as described above includes a step of vertically selecting a compound that inhibits the activity of tryptase from the pharmacophore prepared above. If there is, it is not limited.
  • Virtual selection '' refers to the selection of compounds that inhibit tryptase activity on paper or on a computer without testing the inhibitory effect of the candidate compound, assuming a compound that can be actually assumed. .
  • the step of virtually selecting a compound that inhibits tryptase activity by applying the pharmacophore to computer software is there. More preferably, it is a step of virtually selecting a compound that inhibits novel tryptase activity by analysis, analysis, or using software with any appropriate computer software. Further, the molecule may be designed using any appropriate computer software so as to meet the respective conditions of the pharmacophore.
  • Fig. 2 shows the outline of the above-mentioned screening method.
  • the computer software used may be any software that can extract a chemical function from a ligand and search for a compound that can take a spatial configuration similar to the extracted chemical function. (Accelris) and Sybyl (Tripos). At this time, if it is necessary to classify the compound according to the similarity of the structure and physical properties of the compound, Daylight (Daylight Chemical Information Systems, Inc., Missions on Viejo, CA), etc. It is possible to use the following program.
  • Catalyst (Accelris) as the analysis software is shown below.
  • screening is performed on a compound structure database prepared for computer screening prepared in advance.
  • the information on the pharmacophore is compared with the spatial arrangement of the steric structure of a compound, and it is determined by calculation whether or not the compound satisfies the properties of the pharmacophore.
  • a compound structure database for computer screening is constructed as follows. 1) Three-dimensionalization of the compound: Using a three-dimensional structure generation program such as CONCORD (Tribos) or C0RINA (Molecular Networks GmbH Computerchemie), an initial compound with a standard bond angle and appropriate bond length is used. Generate conformation.
  • CONCORD Tribos
  • C0RINA Molecular Networks GmbH Computerchemie
  • a process of virtually selecting a compound that inhibits a protein by applying it to computer software is that the search target is a subset of all theoretically conceivable compounds. Is received.
  • a database of compounds owned by the company a commercially available compound database, for example, Avali- ble Chemicals Directory (MDL) or a database created by each compound sales company or agency, or a virtual combinatorial synthesis method.
  • MDL Avali- ble Chemicals Directory
  • the database of virtual compounds generated using the above, the database of compounds derived from natural products, the database of pharmaceuticals, etc. are converted and used for computer search.
  • the compound hit by the above-described computer screening is a compound that has a possibility of binding to tryptase, there is a certain probability that the compound may be a compound that inhibits trypsase activity.
  • the step of virtually selecting is preferably exemplified, including the step of drag designing according to the drag designing method of the present invention described later.
  • the computer-based process described above allows for rapid screening of compounds that inhibit trypsinase activity, but the hit compound group has a high probability of having the expected activity. Since not all compounds have activity, it is desirable to actually prepare, synthesize, modify, acquire, or purchase compounds as the next step, and evaluate the prepared compounds experimentally. Required. Therefore, when selecting compounds to be evaluated experimentally from the results of computer screening, it is necessary to determine the number of compounds to be evaluated experimentally, taking into account the expected number of active compounds as a result of the evaluation. There is.
  • a computer-screening program includes an evaluation system, but many evaluation systems have their own unique methods that match the algorithm of the corresponding program. If the activity value of each compound can be obtained as an evaluation system, it is possible to select a compound to be subjected to experimental evaluation based on that value, but an evaluation that can obtain only empirical numerical values instead of activity values There are many systems. On the other hand, assuming that the purpose of computer-based screening is to narrow down the number of compounds to be subjected to experimental evaluation, the number of compounds ranked by the evaluation system is selected by the number that can be used for experiments from the top. Is also good.
  • the probability that the compound selected by computer screening has the expected activity is 5% to 30%
  • about 30 to 200 compounds are required to obtain 10 compounds as an activity controlling substance. What is necessary is just to select, and in order to obtain 50 compounds as an activity controlling substance, about 160 to 1000 compounds may be selected.
  • the activity control compound finally obtained
  • Step (3) is a step of preparing the selected compound. In other words, this is the process of actually preparing the compound that was virtually selected on paper or on a computer in step (2). Even if the use of the candidate compound (2) for inhibiting trybutase is novel, a commercially available product may be purchased as long as it is a known compound, or it may be synthesized using a known method. In the case of a novel compound, it may be appropriately synthesized according to the structure of the compound such as a functional group.
  • Step (2) is a step of measuring the effect of the candidate compound synthesized in (3) on tryptase activity in an in vitro system and / or an in vivo system.
  • an in vitro test or an in vivo test may be used. In vitro tests can be performed more easily. In vivo tests reflect more in vivo, increasing the potential for future drug use.
  • an in vitro test may be performed using the activity measurement method described in the first embodiment of the present invention.
  • the step (2) is not limited to these.
  • the second screening method is as follows: (1) A pharmacophore that satisfies all of the conditions 1 to 4 in Table 1 described in Example 6 described below is applied to a computer software so that a human / 3 tryptase activity that satisfies the pharmacophore is obtained. A method for screening a compound that inhibits tryptase activity, which comprises a step of virtually selecting a compound that inhibits tryptase activity. In addition, (1) the human / 3 trypsinase activity that satisfies the pharmacophore is inhibited by applying the pharmacophore satisfying all of the conditions 1 to 4 in Table 2 described in Example 6 to computer software. A method for screening a compound that inhibits human ⁇ -trypticase activity, comprising a step of virtually selecting a compound to be tested.
  • the pharmacophore described in Table 1 or Table 2 is obtained by analyzing the complex crystal of the fourth embodiment of the present invention and obtaining the same by the method described in Example 7 described later.
  • the pharmacophore conditions 1 and 2 described in Table 1 are conditions that regulate the interaction of the human iS tryptase with the S1 pocket, and are important pharmacophore conditions in inhibiting human i3 tryptase activity. is there.
  • the hydrophobic functional group of Condition 2 of the pharmacophore described in Table 1 is preferably an aromatic ring or a cyclic hydrocarbon. Also, the center of gravity of the hydrophobic functional group is present without causing steric hindrance to tryptase.
  • the pharmacophore condition 3 described in Table 1 is a condition that regulates the interaction with the 90th loop specific to human / 3 trypase.
  • condition 4 of the pharmacophore described in Table 1 is a condition that also defines an interaction with an adjacent tryptase.
  • the adjacent tryptase is a tryptase that has an A-D relationship (also a B_C relationship) described in FIG. 4 described below.
  • the conditions 3 and 4 of the pharmacophore described in Table 1 are important conditions for exhibiting selectivity for human ⁇ trypase.
  • the hydrogen bond accepting group under the condition 3 of the pharmacophore shown in Table 1 is preferably a heteroatom such as oxygen, nitrogen and sulfur, or a group having a high electronegativity such as fluorine. More preferred are carbonyl oxygen, ether oxygen, alcohol oxygen, imine nitrogen and the like.
  • the size of the aromatic ring or cyclic hydrocarbon under the condition 4 of the pharmacophore described in Table 1 is preferably a size obtained by condensing three benzene rings from one benzene ring. More preferably, the size is such that two benzene rings are condensed.
  • the pharmacophore conditions 1 and 2 described in Table 2 are as described in the pharmacophore conditions 1 and 2 described in Table 1.
  • the pharmacophore condition 3 described in Table 2 is a condition that regulates the interaction with the loop No. 90 specific to human) 3 trypase.
  • the pharmacophore condition 4 described in Table 2 is a condition for defining an interaction between two compound molecules bound to two adjacent tryptases.
  • the two adjacent tryptases are two tryptases corresponding to the relationship A—D (equivalent to the relationship B—C) described in FIG. 6 described below.
  • conditions 3 and 4 of the pharmacophore described in Table 2 are important conditions for exhibiting selectivity for human / 3-triple enzyme.
  • the molecule satisfying the pharmacophore described in Table 2 is preferably the other molecule.
  • the C2 axis of rotation is, for example, an axis perpendicular to FIG. 7, passing through the center point of the T-7 ⁇ interaction of the two compounds B identified in FIG.
  • the pharmacophores shown in Tables 1 and 2 have been derived for the first time based on a complex crystal of human] 3 trypticase and a specific ligand.
  • the compound A and the compound B of Example 4 described later are different from the aromatic sulfonamide and the aromatic amide (carpoamide) due to the slight difference between the aromatic sulfonamide and the aromatic amide (carpoamide). It was confirmed that the coupling modes were completely different. This provides a very important finding in conducting structure-activity relationships for trypsinase inhibitors, but it is difficult to derive the fact that only simple crystals of human 3-tryptase are involved. It is.
  • a compound obtained from a pharmacophore that satisfies all of the conditions 1 to 4 described in Table 1 or Table 2 is a compound that has a possibility of binding to human] 3 trypase, and therefore, human jS trypase is used. This raises the possibility of becoming a compound that inhibits the activity.
  • Step (1) is a step in which the pharmacophore shown in Table 1 or Table 2 is applied to computer software to select a compound that satisfies the pharmacophore and inhibits human / 3-trippase activity by means of a valley. .
  • the step of selecting a compound that inhibits a novel tryptase activity from the pharmacophore is as described in the first screening method.
  • the pharmacophore shown in Table 1 or Table 2 was identified from the crystal structure analysis of the complex of human / 3 tryptase and compound A or from the crystal structure analysis of the complex of human i3 tryptase and compound B
  • any software can be used as long as it can perform the operation of docking a ligand to a protein on a computer.
  • DOCK UFS Software
  • Fl exX Tribos
  • Ligand Fit Accelris
  • Ludi Inc.ris
  • an amino acid residue defined in the pharmacophore with which a compound that inhibits tryptase activity interacts provides a pocket that can selectively bind human / 3 tryptase. It is also possible to input the information of the clave into the software and perform computer screening.
  • a grid was generated for the region of the / 3 tryptase molecule that generated the pharmacophore using the GRID program, and the electronic and steric environment at the specified range of receptor residues was determined. Expressed as a scalar value on the grid.
  • a force field such as AMBER to calculate the value of each grid, other force fields may be used, and the present invention is not necessarily limited to AMBER.
  • Screening is performed on a prepared compound structure database for computer screening.
  • the advantage of computer screening is that the search target is a subset of all theoretically possible compounds.
  • a database of compounds owned by the company a database of commercially available compounds, such as Avaliable Chemicals Directory (MDL), a database created by each compound sales company and agency, or a virtual combinatorial synthesis method
  • MDL Avaliable Chemicals Directory
  • the database of virtual compounds generated using the database, the database of compounds derived from natural products, and the database of pharmaceuticals are converted and used for computer search.
  • the compound database is searched using the DOCK program, which is located in the vicinity of the space around the pocket and clave and does not repel the three-dimensional or electronic elements on the grid. Search for compounds that adopt a dimensional conformation.
  • the three-dimensional conformation of the docked compound is optimized by the conformation generation function built into the DOCK program.However, whether the docking was properly performed is determined by the score at the time of docking. Considering the empirical judgment by visual observation, etc., the conformity to the pharmacophore is confirmed, and the hit compound is determined.
  • a series of hit compounds determined to be properly docked in this way are human 0 tryptase with a certain probability as candidates for compounds that selectively inhibit human] 3 trypase activity. Selectively inhibits activity.
  • a consortium capable of screening using a pharmacophore Any software can be used as long as it can extract chemical functions from ligands and search for compounds that can take a spatial configuration similar to the extracted chemical functions on the computer.
  • a module such as Catalyst (Accelris) or Sybyl (Tribos) may be used.
  • Catalyst is shown below.
  • the specified method may be specified by coordinates (x, y, z) or by a set of linear distances connecting each point.
  • the distance relationship between the chemical functions does not necessarily have to be strict.
  • the position of each chemical function is generally defined by a sphere with a radius of 1.5 to 2.0 A centered on each point, or a linear distance connecting each point ⁇ 3 to 4 people However, this value can be changed as appropriate.
  • Screening is performed on a compound screening database prepared in advance for computer screening.
  • the advantage of computer-based screening is that the search target is a subset of all theoretically possible compounds.
  • a database of compounds owned by the company or a commercially available compound database such as the Available Chemicals Directory (MDL) or each compound sales company • Using a database created by a distributor or a virtual combinatorial synthesis method, etc.
  • a database of generated virtual compounds, a database of compounds derived from natural products, and a database of pharmaceuticals are converted and used for computer search.
  • the crystal structure molecule of human 3 tryptase itself can be used as the excluded volume, and it represents the molecular shape of the active conformation of Compound A or Compound B
  • a search formula shape
  • it has the molecular shape of a compound that selectively inhibits human] 3 tryptase activity, and the conditions for chemical functions It is also possible to search for a compound that satisfies the relative spatial configuration defined by a search formula that can satisfy the following.
  • it is possible to increase the hit rate by creating a database of compound groups hit by these search formulas and then applying the database to commercially available docking software for protein structures.
  • the second screening method further includes the following steps.
  • Step (2) is a step of preparing the candidate compound selected in (1)
  • step (3) is a step of measuring the effect of the candidate compound prepared in (2) on tryptase activity.
  • Steps (2) and (3) are as described in the first screening method.
  • a compound array according to an eighth embodiment described later comprising a compound capable of selectively and potentially inhibiting human / 3 tryptase activity, can be prepared.
  • a seventh aspect of the present invention provides a human / 3 trip comprising the following steps: This is a drug design method for a compound that selectively inhibits the enzyme activity.
  • a drug design method for a compound which selectively inhibits human / 3 tryptase activity which comprises the following steps.
  • Step (1) is a step for preparing a fragment group having a functional group corresponding to each condition of the pharmacophore shown in Table 1 or Table 2. For example, fragments having a functional group corresponding to the condition of one pharmacophore are collected to form a fragment group. In addition, fragments having a functional group corresponding to the conditions of another pharmacophore are collected and used as a fragment group. Thus, each fragment group having a functional group corresponding to each condition is created. At this time, a fragment having a functional group satisfying a plurality of pharmacophores, or a fragment having a functional group satisfying a pharmacophore and a functional group satisfying another pharmacophore simultaneously may be collected. The method of collecting fragments is not particularly limited.
  • fragments may be collected from known compounds that inhibit tryptase activity. Add a substituent to one collected fragment, extend or reduce the carbon chain A new fragment may be created by substituting or replacing an atom. In this case, it is more useful to create a fragment that improves a compound that inhibits a known trypasease activity.
  • a water molecule structural water present between trypticase and a compound that inhibits trypticase activity may also play a role in the formation of a complex between the two. Interaction between compounds that inhibit the activity can be identified by, for example, graphics observation.
  • the sites and amino acid residues that form hydrophobic interactions, ionic bonds, and hydrogen bonds can be observed by analyzing the molecular shape given by the active conformation of the compound that inhibits the activity. In this way, the direction of induction that enhances the interaction between a known compound and a nearby amino acid residue is found, or the metabolism, toxicity, etc. are improved without affecting the activity. It is possible to create a new fragment to indicate the appropriate direction above.
  • a fragment is a fragment that binds to the human j3 tryptase S1 pocket and has, for example, a substituent or a ring structure that has a nitrogen atom capable of interacting (preferably ionically) with the hapoxyl group of Aspl 89.
  • This fragment may be further substituted with a halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxyl group or a thioalkyl group, a carboxyl group, or an acyl group or a carboxyalkyl group having 2 to 4 carbon atoms.
  • Fragment L is a fragment that connects both and Ar, and can maintain the conformation of the molecule that matches the pharmacophore.
  • a linear or cyclic structure having 1 to 3 hetero atoms (preferably 1 to 2 nitrogen atoms) and 1 to 5 carbon atoms selected from nitrogen, oxygen and sulfur in the linker.
  • hydrocarbon groups further includes an alkyl group having 1 to 3 carbon atoms, an alkoxyl group, a thioalkyl group or an alkylsulfonyl group, a carboxyl group, or an acyl group, a carboxyalkyl group, or an oxo group having 2 to 4 carbon atoms. It may have a substituent.
  • the end of the linker is preferably an imino group, an alkylene group, or a carbonyl group, assuming the binding of S1 and Ar to the fragment.
  • Fragment Ar is a fragment having an aromatic ring or a cyclic hydrocarbon as its basic structure. It preferably has a monocyclic, condensed or condensed tricyclic ring having 5 to 14 members, and may contain a heteroatom such as nitrogen, oxygen, or sulfur in the ring. Particularly preferred is a bicyclic aromatic ring such as a naphthylene ring. It is preferable that a sulfonyl group, a carbonyl group, an alkylene group, and the like be present in the fragment group, assuming a bond to a linker.
  • aromatic rings or cyclic hydrocarbons are halogen, having 1 to 3 carbon atoms.
  • alkyl group an alkoxyl group or a thioalkyl group, a propyloxyl group, an acyl group or a carboxyalkyl group having 2 to 4 carbon atoms, an oxo group or an amino group.
  • the fragment S i is the same as the fragment S i shown in Table 3 except that halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxyl group or a thioalkyl group, a lipoxyl group, or an acryl group or a carboxyalkyl group having 2 to 4 carbon atoms. It may be a fragment substituted with a group or the like.
  • Fragment L is the same as fragment L shown in Table 3, except that it further has an alkyl group having 1 to 3 carbon atoms, an alkoxyl group, a thioalkyl group or an alkylsulfonyl group, a carbonyl group, or an acryl group or a carboxyalkyl group having 2 to 4 carbon atoms. Alternatively, it may have a substituent such as an oxo group.
  • the carbon of the hydrocarbon group of fragment L shown in Table 3 may be further substituted with one or two hetero atoms selected from nitrogen, oxygen and sulfur. In this case, the total number of nitrogen atoms in the fragment is preferably one or two.
  • Fragment Ar is obtained by adding a halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxyl group or a thioalkyl group, a carboxyl group, a C 2-4 carbon atom to the aromatic ring or cyclic hydrocarbon of the fragment Ar shown in Table 4. It may be substituted with an acyl group, a carbonyloxy group, an oxo group or an amino group.
  • the aromatic ring or cyclic hydrocarbon of the fragment Ar shown in Table 4 is a different monocyclic or condensed 5- to 14-membered member which may contain a heteroatom such as nitrogen, oxygen or sulfur. ring Alternatively, it may be replaced by a condensed three ring.
  • a fragment in which an aromatic ring or a cyclic hydrocarbon is replaced by a bicyclic aromatic ring such as a naphthalene ring or a benzothiophene ring.
  • the pharmacophore described in Table 2 it is possible to perform drug design by defining that two molecules of the adjacent trypase are inhibited by two molecules of the same compound. For example, one compound binds to the S1 pocket of one tryptase and the other compound binds to the S1 pocket of the other tryptase. And it is a drug design that specifies that compounds have an — ⁇ interaction by giving the compounds an aromatic amide group.
  • the adjacent trypase is a trypase that corresponds to the relationship A to D (the relationship of ⁇ to C) described in FIG. 4 described below.
  • Step (2) is a step of combining the fragments selected one by one from the fragment group created in (1) to construct a compound model.
  • a compound model may be constructed by combining fragments selected one by one from each fragment group determined in 1) on paper.
  • the compound is modeled using computer software. Any software may be used as long as it can construct the structure of the compound. For example, CombiLibMaker, a module of Ludi (Accelris) or Sybyl (Tripos), may be used.
  • CombiLibMaker a module of Ludi (Accelris) or Sybyl (Tripos)
  • By constructing a model of a compound using computer software not only can a large number of models be constructed in a short time, but it is also convenient when the compound is used in the process of (3).
  • each flag selected from each fragment group described in Tables 3 and 4 This is the step of building a model of the compound by binding the components.
  • Binding fragments includes directly binding the fragments, and using a linker between the fragments to release the linker and bind the fragments.
  • the linker is not particularly limited. Examples thereof include a hydrocarbon group having a straight chain or a side chain, and a group in which the hydrocarbon group is substituted with a hetero compound.
  • the method for drug design of the present invention preferably includes the following steps.
  • Step (3) is a step of using the above-mentioned pharmacophore for computer software to select a compound that selectively inhibits human iS tryptase activity among the compounds constructed in (2).
  • the compound group modeled in (2) is used for the combination software as described in the sixth embodiment of the present invention to select a compound.
  • the selected human i3 tryptase activity is selectively and potentially inhibited (possibly inhibited) as a library. It can be used to screen for compounds that inhibit it.
  • the library 1 is a set of compounds having a human] 3 tryptase inhibitory activity with a considerably higher probability than a general database.
  • the drug design method of the present invention further comprises the following steps: It is preferable to screen for compounds that selectively inhibit tripase activity.
  • the probability of hit compounds is higher than screening the effect on human / 3 trypsinase activity using a random compound.
  • step (2) is a step of preparing the compound selected in step (3).
  • the steps (2) and (3) can be performed simultaneously.
  • a compound model may be constructed by applying the pharmacophore to the computer and binding the pharmacophore.
  • a pharmacophore may be provided to the computer software.
  • the program may be designed so that a bond that satisfies the pharmacophore can be formed.
  • a compound array consisting of a compound capable of selectively and potentially inhibiting human) tripsease activity described in an eighth embodiment described below is prepared. be able to.
  • An eighth aspect of the present invention is a method for preparing a compound array comprising a compound capable of selectively and potentially inhibiting human jS trypsinase activity, wherein the pharmacophore described in Table 1 is prepared by computer-software.
  • the present invention relates to a method for preparing a compound array comprising a compound capable of selectively and potentially inhibiting human tryptase activity, wherein the pharmacophore described in Table 2 is used for computer software to satisfy the pharmacophore.
  • compounds that selectively inhibit human tryptase activity are virtually selected, and the selected compounds are actually prepared in real life and combined to form a compound array.
  • a potentially inhibitory compound is a compound that theoretically inhibits and that has a higher probability of inhibition than a random compound in actual in vitro and Z or in vivo tests.
  • the compound prepared by the method for preparing a compound array of the present invention is a compound that satisfies the pharmacophore conditions shown in Table 1 or Table 2, and is therefore a compound that theoretically inhibits.
  • the preparation method of the present invention includes a method of adding a new compound to an existing compound array or a compound array being prepared.
  • a compound array is a collection of real, real compounds prepared for in vitro and / or in vivo testing. Usually, it is held on a support such as a plate. For example, screening plates, aligned samples Tubes and the like.
  • the production method of the present invention is as described in the sixth and seventh aspects of the present invention.
  • a method of preparing a compound array which includes a drug design method including a step of selecting one fragment from each of the fragment groups described in Tables 3 and 4 and binding the selected fragments to construct a compound model It is.
  • the compound array prepared by the preparation method of the present invention is composed of compounds that can selectively inhibit human JS tryptase activity, human i3 tryptase activity is selected from a conventional compound array containing random compounds. Compounds that inhibit the activity can be obtained with a considerably high probability.
  • a ninth aspect of the present invention is a library of compounds capable of selectively and selectively inhibiting human
  • the database of the compound of general formula S, 1L-1Ar constructed from the fragment groups shown in Tables 3 and 4 was used for computer software, and the pharmacophore shown in Table 1 or Table 2 was used.
  • a library generally refers to a mixture or aggregate (group) of compounds, such as compounds that inhibit a putative ligand or activity of a protein, and compounds that activate a compound, and refers to a plurality of compounds enclosed by an envisioned concept.
  • the library 1 of the present invention is a collection of compounds that can selectively and selectively inhibit human i3 tryptase activity obtained by computer screening.
  • the database of compounds constructed from the fragment groups shown in Tables 3 and 4 The library 1 can be obtained by applying the pharmacophore shown in Table 1 or Table 2 to computer software. A specific method for obtaining the library of the present invention is as described in the seventh embodiment of the present invention.
  • the number of candidate compounds contained in the library may vary slightly depending on the computer software or on the method of applying the pharmacophores shown in Table 1 or Table 2 to the computer software, such as the search formula. But this difference cannot be an essential difference.
  • a compound having tryptase inhibitory activity can be considerably more probable than a library or a database containing conventional random compounds. Can be obtained at
  • the library of the present invention may not include all candidate compounds obtained by computer software. Libraries may also be included that screen for compounds that inhibit tryptase activity in a certain manner or randomly reduce the number of candidate compounds. It also includes libraries created with other candidate compounds. In this case, a library in which the other candidate compounds included are less than half of the library is preferred. It is more preferably at most 174, particularly preferably at most 10: 1. Such a library has an advantage that it can suitably cope with screening of necessary compounds from various viewpoints.
  • a tenth aspect of the present invention is a pharmacophore described in Table 1 or Table 2.
  • the method for obtaining the pharmacophor is described in Example 6 below.
  • the compound array of the eighth aspect of the present invention can be prepared using the pharmacophore.
  • the library of the ninth aspect of the present invention can be obtained.
  • the present invention provides an electronic medium recording or storing or storing the pharmacophore described in Table 1 or Table 2, or a programmed program.
  • the electronic medium may be a primary storage medium of an electrical medium called a memory or a semi-permanent storage medium such as a floppy disk, hard disk, optical disk, magneto-optical disk, or magnetic tape.
  • These electronic media are computer-readable electronic media, and can be used, for example, on software used for compound screening. It is also possible to program the pharmacophore listed in Table 1 or Table 2 directly into a software or other program used for compound screening, and to create a program on a computer independently of other programs. It is also possible. These programs are held semi-permanently and can be used alone or in conjunction with other software for compound screening.
  • An eleventh aspect of the present invention is any one of the following compounds or pharmaceutically acceptable salts thereof that inhibits the human / 3 tryptase activity satisfying the pharmacophore described in Table 1 or Table 2. .
  • the tryptase-eluted fraction was collected at 37 ml and concentrated to about 34 ml with Ultrafele5.
  • 1.7 M NaCl, 1 OmM MES pH 6.0 was added about 10 times to the concentrated H content, and the mixture was further centrifuged and concentrated. This operation was repeated three times.
  • 680 il of a purified purified sugar chain-cleaved tryptase from which the released sugar chains and the heparin derived from the raw material were partially removed was obtained. '
  • Buffer solution (lO OmM Tris-HC1 pH 7.5, 200 ng / ml heparin) 60 1 Recombinant tryptase or sugar chain-cleaved tryptase adjusted to 100 ng / m1 was added to 20 BABIM1I dissolved at each concentration of 0.01, 0.03, 0.1 and 0.3 g / m1 or DMSO1 ⁇ as a control was added to the mixture. Thereafter, add 20 1 of 0.5 mM substrate (Boc-Ph-Ser-Arg-MCA), react at 25 ° C for 1 hour, and stop the reaction by adding 100% 1 of 20% acetic acid. Was.
  • the value of before was determined by adding BABIM or DMSO, adding 1001 of 20% acetic acid, then reacting the substrate at 201 calories and reacting at 25 for 1 hour, and measured the fluorescence.
  • the activity of the enzyme was evaluated by the following formula.
  • the enzymatic reaction results were expressed as the difference ( ⁇ ) between the after value and the before value.
  • tryptase activity 1U “Amount of tryptase that increases ⁇ fluorescence count by 1,000,000 in 60 minutes”
  • the suppression rate was evaluated by the following equation.
  • Inhibition rate (%) (A-B) / (A-C) X 100 (%)
  • the trypsinase prepared in Example 1 was concentrated by centrifugal ultrafiltration to prepare a protein solution having the following composition. 5. 5 mgZmL sugar chain-cleaved trypase, 1.7 mol / L sodium chloride, 10 mmol / L 3- (N-morpholino) propanesulfonic acid (pH 6.0).
  • the complex of tryptase and compound A is obtained by adding 10 mmol / L compound A, 1.7 mol 1 ZL sodium chloride, 1 Ommo 1 ZL 3- (N-morpholino) propanesulfonic acid ( ⁇ 6 ⁇ 0), 20 V ⁇ 1% 1,4-dioxane was added in an amount of 20 L.
  • the crystallization plate used was a 24-well plate (limb plate) for cell culture with microbridge (Nampton Research). 800 L of 3 OwZv% polyethylene glycol 4000, 0.2 mol / L ammonium acetate and 0.1 mol LZ acetate buffer (pH 5.0) were placed in a plate well as a reservoir solution.
  • the crystallization solution was prepared by mixing a complex solution of tryptase and compound A, a reservoir solution, and 3 Ow / v% 1,5-diaminopentane at a ratio of 5: 4: 1, and then put 2 on the microbridge. It was left still. Such crystallization drops were prepared for one plate at a time, that is, 24 crystallization drops were prepared.
  • SP ri ng—8 was performed at Bumline, Hyogo (BL 24XU).
  • the data was collected using a R-AX ISV imaging plate detector (Rigaku), and a range of 180 degrees was measured at a vibration angle of 1 degree by vibratory photography. Measurement results 2.
  • a data set with a resolution of 4 people was obtained.
  • Data integration and intensity calculations are provided by MOSFLM (A. Jones,. Bartels & P. Schwager (1977) in 'The Rotation Method in Cry stallography', UW Arndt & A ⁇ Wonacoit, eds, North Holland Publishing Co.).
  • the structure factor was calculated using TRUNCATE (Frencheta 1., Acta Cryst. 21 (1978), 517-525).
  • Table 7 shows the amino acid residues of human jS tryptase necessary for the construction of the pharmacophore of Example 6 described later, the amino acid residues around it, and the coordinates of the final model of compound A.
  • Table 7 shows the coordinates in the PDB file format of the Research Col laboratory for Structural Bioinformatics (RCSB) obtained from the X-ray structural analysis of the complex of human) 3 trypase and compound A.
  • RCSB Structural Bioinformatics
  • Example 4 A crystal of tryptase alone selected as a suitable size for the diffraction experiment in synchrotron radiation was obtained by dissolving 8.75 mmol / L of compound B in 3 Ow / v% polyethylene glycol 4000, 0.2 mol 1 ZL ammonium acetate, 1. The complex was crystallized by soaking by immersion in a solution of OmolZL NaC 0.1 mo1 / L acetate buffer pH 5.0. Immersion was performed at 20 ° C for 24 hours to obtain composite crystals. In a later-described diffraction experiment, a composite crystal having a size of 0.1 ⁇ 0.1 ⁇ 1 ⁇ 0.3 mm 3 was used.
  • Example 4 The X-ray diffraction experiment was performed in the same manner as described in Example 4, and as a result of the measurement, a data set having a resolution of 2.0 A was obtained. Data analysis was performed in the same manner as described in Example 4.
  • the final model has an R factor of 21.3% (R free factor is 24.1%) r.m.s.deviation of 0 ⁇ 005769 (bonds), 1.36917 (an g 1 es).
  • Table 8 shows the amino acid residues of human ⁇ -tryptase necessary for construction of the pharmacophore of Example 6 described later, the surrounding amino acid residues, and the coordinates of the final model of compound II.
  • Table 8 shows the coordinates in the RCSB PDB file format obtained by X-ray structural analysis of the complex of human (3) trypase and compound ⁇ .
  • the pharmacophores in Table 2 described later can be extracted.
  • 6 and 7 show the Ripon diagrams of the results of analysis of human / 3 tryptase and compound B.
  • a complex crystal of tryptase and a compound can be obtained in only one day by using the soaking method. If synchrotron radiation is used, the measurement time per crystal is about 3 hours. The subsequent analysis uses the molecular replacement method, so it takes about 2 hours. In the shortest two days after starting soaking, the candidate compound that inhibits trypticase activity used for soaking is a tryptase molecule. It can be determined whether or not to combine.
  • Fig. 8 As a three-dimensional diagram of the amino acid residues of human / 3 tryptase interacting with compound A, and in Fig. 9 as a three-dimensional diagram of the amino acid residues of human i3 trypticase and compound A. .
  • the conditions for this site in the pharmacophore were defined as the region where hydrogen bonding is possible at the distance between Aspl89 and the N atom of benzylamine. That is, it was defined that the nitrogen atom was located within 3.21 ⁇ 0.5 people around the oxygen atom in the side chain of Aspl89.
  • the conditions that express the hydrophobic environment in the S1 pocket of the pharmacophore are as follows. It was defined by the position of the center of gravity of the functional group.
  • the hydrophobic functional group is an aromatic ring or a cyclic hydrocarbon, and the center of gravity of the hydrophobic functional group is present without causing steric hindrance to tryptase.
  • the sulfonamide of compound (2) forms an interaction with the 90th loop specific to human) 3 tryptase, and is an important site for exerting selectivity for human i3 trypase. Direct interactions were hydrogen bonding with the main chain of Ala97 and hydrogen bonding with the side chain of Gln98.
  • the conditions for this site in the pharmacophore are defined by the presence of a hydrogen-bond acceptor within 2.9 ⁇ 0.5 of the nitrogen atom of the Ala97 main chain or within 3.2 ⁇ 0.5 of the N ⁇ atom of Gln98. did.
  • the hydrogen bond accepting group was preferably a heteroatom such as oxygen, nitrogen or sulfur, or a group having a high electronegativity such as fluorine. Specifically, they were carbonyl oxygen, ether oxygen, alcohol oxygen, imine nitrogen and the like.
  • Fuarumakofoa is, Tyr95, Thr96 and distances 6.9 ⁇ 1.4 people each from C of Glu217 adjacent preparative ribs evening over Ze, 5.1 ⁇ 1.4 people, 7.7
  • the size of the aromatic ring or cyclic hydrocarbon was preferably a size obtained by condensing three benzene rings from one benzene ring. More preferably, the size was such that two benzene rings were condensed.
  • the amino acid residues of human / 3 tryptase useful for the interaction analysis identified from the crystal structure analysis of human 3 tryptase and compound A complex, the definition of the compound, the interaction mode, and the conditions for each site of the pharmacophore The summary is shown in Table 1.
  • Fig. 10 shows a schematic diagram of the pharmacophore.
  • FIG. 11 is a diagram
  • FIG. 12 is a diagram of the amino acid residues of human tryptase and compound B.
  • the benzylamine site of compound B also has an ionic bond with Aspl 89 of the S1 pocket, similar to compound A, and the benzene ring with benzylamine is hydrophobic in the hydrophobic environment of the S1 pocket. It was found to have an interaction. As described above, this region is a part that regulates the strength of inhibiting jS tryptase, and is a selective component for serine proteases with a hydrophobic S1 pocket bottom, such as elasase. However, rather than interacting with sufficient selectivity for trypsin-type serine protease, it may be regarded as an important interaction for strongly inhibiting 3 tryptase. did it.
  • the conditions for this site in the pharmacophore were defined as a region capable of hydrogen bonding at the distance between Aspl 89 and the N atom of benzylamine. That is, it was defined that the nitrogen atom was located within 3.21 ⁇ 0.5 A centering on the oxygen atom of the side chain of Aspl 89.
  • the conditions that express the hydrophobic environment in the S1 pocket of the pharmacophore are as follows: Glnl 92, Trp215, and Gly219 are at distances of 5.2 ⁇ 1.4, 3.9 ⁇ 1.4, and 6.1 ⁇ , respectively, from C. 1. It was defined that the center of gravity of the hydrophobic functional group was located in the space formed by four people. Preferably, the hydrophobic functional group is an aromatic ring or a cyclic hydrocarbon, and the center of gravity of the hydrophobic functional group is present without causing steric hindrance to tryptase.
  • the amide of compound B formed an interaction with the tryptase-specific loop 90, and was an important site for exerting selectivity for human] 3 tryptase. The direct interaction was a hydrogen bond with the side chain of Gln98.
  • the condition for the site is 3.3 ⁇ 0.5 from the N ⁇ atom of Gln98. It was specified that a hydrogen bond acceptor (Hydrogen-bond Acceptor) was located within the region.
  • the hydrogen bond accepting group was preferably a heteroatom such as oxygen, nitrogen or sulfur, or a group having a high electronegativity such as fluorine. Specifically, it was carbonyl oxygen, ether oxygen, alcohol oxygen, imine nitrogen and the like.
  • the aromatic ring bound to the amide exerted a tryptase inhibitory activity in a very characteristic manner by directly interacting with an adjacent molecule. Since this binding mode is a binding mode formed only by tetrapterase tryptase, it is important information for searching or designing compounds that selectively inhibit i3 tryptase activity. Met.
  • the molecule that satisfies the pharmacophore has a positional relationship of 180 ° C. rotation about the C 2 rotation axis with another molecule of the same compound.
  • Table 2 summarizes the amino acid residues useful for the interaction analysis identified from the crystal structure analysis of the complex of human) 3 tryptase and compound B.
  • Figure 13 shows a schematic diagram of the pharmacophore.
  • the pharmacophore of Table 1 or the pharmacophore of Table 2 obtained in Example 6 was subjected to computer screening for a compound capable of binding to human / 3 trypsinase using DOCK as analysis software.
  • Example Compound 5 described later is defined as an example of a compound matching Table 1
  • Example Compound 12 described below is defined as an example of a compound matching Table 2
  • Examples described later are respectively described. went.
  • a radius of 1.5 was placed around the oxygen atom of the sulfonamide.
  • a straight line was drawn in the direction of the lone pair of the oxygen atom from the sulfonamide oxygen atom, and a sphere with a radius of 1.5 was placed around the position three people away from the sulfonamide oxygen atom. These two spheres were used as characteristic spheres corresponding to the Hydrogen-bond Acceptor.
  • a radius sphere was placed around the center of gravity of the benzene ring on the sulfonamide side of the naphthalene ring. Also, a straight line is drawn from this center of gravity in a direction perpendicular to the plane of the aromatic ring. Radius 1. Place 5 balls. These two spheres are characteristic spheres equivalent to Ring Aromatic.
  • Figure 14 shows the characteristic sphere.
  • a sphere with a radius of 1.5 centered on the nitrogen atom of the aminomethyl group of Compound B was used as a characteristic sphere equivalent to Positive Ionizable.
  • a sphere with a radius of 1.5 was placed around the oxygen atom of the amide bond.
  • a straight line was drawn in the direction of the lone pair of the oxygen atom from the sulfonamide oxygen atom, and a sphere with a radius of 1.5 was placed around the position three people away from the sulfonamide oxygen atom.
  • These two spheres were used as characteristic spheres equivalent to the Hydrogen-bond Acceptor.
  • a ball with a radius of 1.5 was placed around the center of gravity of the thiophene ring of benzothiophene.
  • a straight line was drawn from this center of gravity in a direction perpendicular to the plane of the aromatic ring. Eye radius 1. Placed five spheres. These two spheres are characteristic spheres equivalent to Ring Aromatic.
  • Figure 15 shows the characteristic sphere.
  • Figure 16 shows the characteristic sphere.
  • Table 11 shows the relative positional relationships in the three-dimensional space of the chemical functions defined above.
  • Example Compound 3 described below matches the pharmacophore described in Table 1 (2)
  • Example Compound 6 described below matches the pharmacophore described in Table 2 (2)
  • an example compound described later 4 was virtually selected as an example of the compound (2) -3 which matches the pharmacophore described in Table 2, and the examples described later were respectively performed.
  • S A fragment that binds to the S1 pocket.
  • an aromatic ring having a nitrogen atom capable of interacting with (preferably ion-bonding with) a carboxyl group of Aspl 89, or an aromatic ring containing nitrogen in the ring structure, or a cyclic hydrocarbon having the substituent is used.
  • This fragment may be further substituted with halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxyl or thioalkyl group, a propyloxyl group, or an acryl or carboxyalkyl group having 2 to 4 carbon atoms.
  • a linear or cyclic linker having 1 to 3 hetero atoms (preferably 1 to 2 nitrogen atoms) and 1 to 5 carbon atoms selected from nitrogen, oxygen, and sulfur inside the linker.
  • a hydrocarbon group further includes an alkyl group having 1 to 3 carbon atoms, an alkoxyl group, a thioalkyl group or an alkylsulfonyl group, a lipoxyl group, or a carbon number. It may have 24 substituents such as an acyl group, a carboxyalkyl group or an oxo group.
  • the end of the linker is preferably an imino group, an alkylene group, or a carbonyl group, assuming the binding of and to the fragment of Ar.
  • a fragment having an aromatic ring or cyclic hydrocarbon as its basic structure It preferably has a monocyclic, condensed or condensed tricyclic ring having 5 to 14 members, and may contain a hetero atom such as nitrogen, oxygen, or sulfur in the ring. Particularly preferred is a bicyclic aromatic ring such as a naphthalene ring. Assuming a bond to a linker, it is preferable that a sulfonyl group, a carbonyl group, an alkylene group and the like are present in the fragment group.
  • the aromatic ring or cyclic hydrogen is a halogen, an alkyl group having 13 carbon atoms, an alkoxyl group or a thioalkyl group, a propyloxyl group, an acyl group or a carboxyalkyl group having 24 carbon atoms, an oxo group or an amino group. May be substituted.
  • fragments that can be used as SL Ar desirable partial structures were collected from a compound structure database for computer screening prepared in advance.
  • Table 3 shows examples of fragments corresponding to L and L
  • Table 4 shows examples of fragments corresponding to Ar.
  • the two-dimensional structure was input to Catalyst, and the conformation was automatically generated from the most stable conformation with the upper limit of the generation energy of 2 kcal / mol, and converted to a Catalyst database.
  • computer screening was performed using Dock or Catalyst.
  • the hit compound was selected by visually judging the score value of the evaluation function and the binding state, and comprehensively judging both.
  • Catalys a compound having a value of the evaluation function equal to or less than a certain value was selected as a hit compound.
  • Example Compounds 7, 8, and 9 described below are examples of compounds that match the pharmacophores described in Table 1, and Example Compounds 10 and 11 described below are pharmacophores described in Table 2. As examples of compounds that conform to the following, Examples described later were performed.
  • Example Compound 1 is Compound A
  • Example Compound 2 is Compound B.
  • Table 12 shows the structural formulas of Example Compound 1 to Example Compound 12.
  • Example compound 4 Example compound 1 o
  • Example Compound 1 Example Compound 1
  • Compound B Example Compound 2
  • Example Compound 2 Example Compound 2
  • Example Compound 2 Example Compound 2
  • the nuclear magnetic resonance (NMR) spectrum is JEOL JNM-EX270 (J EOLJ NM-EX270) FT-NMR (* is shown on the data, manufactured by JEOL Ltd.) or JEOL J NM-LA300 (J EOL JNM-LA300) ) Measured using FT-NMR (manufactured by JEOL Ltd.).
  • Step 1 Synthesis of 3 -— [4- (N-tert-butoxycarbonylaminomethyl) phenyl] propanal
  • Step 3> Synthesis of N— [2-—N- [3 -— [4- (aminomethyl) phenyl] propyl] amino] ethyl] -12-naphthylenesulfonamide
  • morpholine 20 mL
  • Example compound intermediate number 2-3 was obtained.
  • step 2 To a solution of the compound obtained in step 1 (0.30 g) in methylene chloride (10 mL) were added triethylamine (69 L) and then acetyl chloride (37 L) under ice-water cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was poured into water and extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (0.34 g, Intermediate No. 2-2 of Example compound).
  • Step 1 Synthesis of N— [2-—bis [3- [4- (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] amino] ethyl] trifluoroacetamide
  • Example Compound 2 was prepared using the compound (0.16 g) obtained in Step 1 of the synthesis of Example Compound 1 and N- (2-aminoethyl) trifluoroacetamide hydrochloride (59.Omg). The reaction was conducted in the same manner as in Step 1 of the synthesis of, to obtain the title compound (0.14 g, Example compound intermediate number 411).
  • Step 2> Synthesis of bis [3 -— [4 -— (N-tert-butoxycarbonylaminomethyl) phenyl] propyl]-(2-aminoethyl) amine
  • Step 2> Synthesis of N— [2- [N- [2 -— [4- (aminomethyl) phenoxy] ethyl] amino] ethyl] -1-2-naphthalenesulfonamide
  • Example Compound 2 using benzo [b] thiophene-2-fluorocarboxylic acid (1.53 g) and 2- (N-tert-butoxycarbonyl N-methylamino) ethylamine (1.0 g) The reaction was carried out in the same manner as in Step 3 of Step 3 to obtain the title compound (1.86 g, Example compound intermediate No. 6-2).
  • Step 4 Synthesis of N- (4-piperazinylphenyl) 1- [1- (4-phenyl) benzenesulfonyl 4-piperidine] Potassium lipoxamide trifluoroacetate Compound obtained in Step 3 (0 To 12 g) was added anisol (54 D, then 0.39 mL of trifluoroacetic acid under ice water cooling), and the mixture was stirred at room temperature overnight.Ether was added to the reaction mixture, and the precipitated precipitate was collected by filtration and washed with ether. The title compound (0.10 g) was obtained by washing.
  • Step 1 Synthesis of 4- (tert-butoxycarbonylamino) 1-11-[(4-phenyl) benzenesulfonyl] piperidine
  • Step 3 Synthesis of N- [1-1 (4-phenyl) benzenesulfonyl 4-piberidyl] -1- (4-guanidinobenzene) lipoxamide methanesulfonate
  • Compound obtained in Step 2 (0 llg) and 4-guanidinobenzoic acid methanesulfonate (0.20 g) in pyridine (4 mL) were added with N, N'-dicyclohexylcarposimide (0.16 g) and stirred at room temperature overnight.
  • N- (2-Aminoethyl) trifluoroacetamide hydrochloride (4.43 g) and pyridine were added to a toluene (10 OmL) solution of the compound (303 g) obtained in Step 1 of the synthesis of Example Compound 1. (0.93 mL) was added. The solvent was distilled off under reduced pressure, and toluene (8 OmL) was added to the obtained residue. The solvent was further distilled off under reduced pressure, and this operation was repeated twice. Methylene chloride (5 OmL) was added to the obtained residue, and sodium triacetoxyborohydride (4.87 g) was added thereto, followed by stirring overnight at room temperature under a nitrogen atmosphere.
  • Step 2> Synthesis of N— [2 -— [N—tert—butoxycarpone] N— [3-—4- (N-tert-butoxycarponylaminomethyl) phenyl] propyl] amino] ethyl] trifluoroacetamide
  • Step 5> Synthesis of N— [2 -— [N— [3-—4- (aminomethyl) phenyl] propyl] amino] ethyl] mono (1-1-chloro-2-naphthalene) sulfonamidini hydrochloride
  • the compound obtained in Step 2 of the synthesis of Example Compound 2 (50 Omg) in chloroform (5 mL) was added with 2,3-naphthalenedicarboxylic anhydride (34 ⁇ Omg), and the mixture was refluxed for 3 hours.
  • Step 2> Synthesis of N— [2 -— [N— [3- [4- (aminomethyl) phenyl] propyl] -1-N-methylamino] ethyl] -15-indolecarpoxamidoni hydrochloride
  • Table 13 shows 1 H-NMR data of the compound of the present invention obtained from the synthesis of Example Compound 1 to the synthesis of Example Compound 12, and Table 14 shows the —NMR data of intermediates of the Example compound. .
  • Example compound intermediate No. 11 means an intermediate obtained by “Step 1 of synthesis of Example compound 1”.
  • Example 3 The measurement of tryptase activity was performed by the method described in Example 3. Instead of BABIM, the compound synthesized in Example 8 was added at 0.03 lugZm1-: L0 g / m1 at a three-fold common ratio. Inhibition against human ⁇ trypsinogen evening one peptidase example compounds 10 activity IC 5. Is 0.09. Further, example compounds 1-9, inhibitory activity IC 5 against 1 1 and 1 2 of the human 3 Ta Riputaze. Were all less than 10 / xM. Industrial applicability
  • the present invention makes it possible to easily obtain tryptase crystals having an active and cleaved sugar chain, or complex crystals of this trypase and a substance having affinity. If used, compound arrays, libraries or pharmacophore of compounds having tryptase inhibitory activity can be easily obtained. In addition, screening or drug design of compounds having trypticase inhibitory activity can be carried out using these, so that candidate compounds can be appropriately obtained.
  • ATOM 4542 CA GLY C 100 60.152 4.709 0.698 1.00 19.60 C

Abstract

It is intended to provide a compound array, a library or a pharmacore of a compound which is obtained by subjecting a natural tryptase or a recombinant tryptase in the undenatured state to sugar chain cleavage and shows uniformity by Coomassie-staining in SDS-PAGE, and a screening method or a drug designing method of a compound having a tryptase inhibitory activity with the use of the same. Thus, tryptase crystals which sustain the activity and the sugar chain of which has been cleaved or crystals of a complex with the tryptase and a substance having an affinity thereto can be easily obtained. Using these crystals, a compound array, a library or a pharmacore of a compound having a tryptase inhibitory activity can be easily obtained. By using them, moreover, a compound having a tryptase inhibitory activity can be screened or drug-designed. Thus, a candidate compound can be appropriately obtained.

Description

明 細 書  Specification
結晶性新規トリプ夕一ゼおよびその利用 New crystalline trypticase and its use
技術分野 Technical field
本発明は、 糖鎖を切断して得られる活性を有するトリプ夕一ゼ、 及びその 製法、 該トリプタ一ゼを用いる結晶化トリプ夕一ゼの製法、 該トリプタ一ゼと特 定のトリプ夕ーゼ活性を阻害する化合物との複合体結晶に関する。 また、 該トリ プタ—ゼを利用するトリプタ一ゼ活性を阻害する化合物のスクリーニング方法、 該トリプタ一ゼと特定のトリプターゼ活性を阻害する化合物との複合体結晶の解 析から得られるフアルマコフォア、 該フアルマコフォアを利用したスクリーニン グ方法またはドラッグデザィン方法、 及び該ドラッグデザィン方法により得られ るライブラリ一に関する。  The present invention relates to a trypase having activity obtained by cleaving a sugar chain, a method for producing the same, a method for producing a crystallized trypase using the tryptase, the trypase and a specific trypase. The present invention relates to a complex crystal with a compound that inhibits zein activity. A method for screening a compound that inhibits tryptase activity using the tryptase; a pharmacophore obtained by analyzing a complex crystal of the tryptase and a compound that inhibits a specific tryptase activity; The present invention relates to a screening method or a drag design method using the method, and a library obtained by the drag design method.
背景技術 Background art
トリプターゼ （酵素番号 3. 4. 2 1. 5 9) は、 トリプシン、 トロン ビン、 ファクター X a (FX a) 、 カリクレインなどと同様、 セリンプロ ティナ一ゼに属する蛋白分解酵素である。 《 1、 I I、 β I , I I、 I I I、 ( I、 I I、 5 I , εなどのトリプターゼ cDNAが得られており、 これらのうち αトリプタ一ゼ、 トリプ夕一ゼは肥満細胞や好塩基球の顆粒中に特異的に局在 する。 aトリプターゼと ;3トリプターゼは 93 %のアミノ酸配列の相同性を有す るが、 aトリプ夕ーゼは恒常的に肥満細胞から分泌されているのに対し、 j6トリプタ一ゼは肥満細胞の脱顆粒によって特異的に細胞外へ分泌されるという 相違点がある (シュヴァルッ (Schwartz) ら、 ジャーナル、 ォブ、 クリニカル、 インべスティゲ一ション （J. C l i n. I nv e s t. ) 第 96巻、 2702 頁、 1995年） 。 Tryptase (enzyme number 3.4.2.59) is a proteolytic enzyme belonging to serine proteinase, like trypsin, thrombin, factor Xa (FXa), and kallikrein. << 1, II, βI, II, III, (I, II, 5I, ε, etc. tryptase cDNAs have been obtained. Of these, α-tryptase and trypticase are mast cells and basophils. A Tryptase and; 3 tryptase have 93% amino acid sequence homology, whereas a tryptase is constantly secreted from mast cells. On the other hand, The difference is that j6 tryptase is secreted extracellularly by mast cell degranulation (Schwartz et al., Journal, Ob, Clinical, Investigation (J. Clin). Inv es t.) 96, 2702, 1995).
ヒト 3 トリプ夕一ゼは N i l e s、 Ma f f i t tら （B i o t e c h n o l . Ap p l . B i o c h em. 28巻、 1 25頁、 1998年） により クローニングされ、 リコンビナントヒト iSトリプターゼが得られている。 得られ たリコンビナントヒト 3トリプ夕ーゼは、 33 kDa〜50 kD aまでの分子量 を示し不均一である。 トリプタ一ゼを熱変性後に、 PNG a s e Fや En do Hによって処理するとコア蛋白が 33 kD aになることを記載してい る。 また、 同一発明者等による WO 99/60139号公報にも同様の記載があ るが、 トリプ夕ーゼの糖鎖の切断条件の記載はない。  Human 3 trypsinase has been cloned by Niles, Maftit et al. (Biotechnol. Appl. Biochem. 28, 125, 1998), and recombinant human iS tryptase has been obtained. The obtained recombinant human 3 trypase has a molecular weight of 33 kDa to 50 kDa and is heterogeneous. The document states that the core protein becomes 33 kDa when treated with PNGaseF or EndoH after heat denaturation of tryptase. A similar description is also given in WO 99/60139 by the same inventors, but there is no description of the conditions for cutting the sugar chain of trypsinase.
しかし、 これらの文献には未変性のまま糖鎖を切断して得られたトリプタ一ゼ は開示されていない。 さらに、 糖鎖切断処理されて活性を維持している トリプターゼについても開示されていない。  However, these documents do not disclose tryptase obtained by cleaving a sugar chain in a native state. Furthermore, there is no disclosure of a tryptase which maintains its activity after being subjected to a sugar chain cleavage treatment.
また、 トリプターゼは病態との関連性が示唆されている。 例えば、 蜂ァレ ルギ一など全身性アナフィラキシー性ショック患者において、 血中 iSトリプ夕一 ゼ含量は持続的に上昇する （シュヴァルッ （Schwartz) ら、 ニュー、 イングラン ド、 ジャーナル、 ォブ、 メディスン (N. Eng l . J. Me d. ) 、 第 316 巻、 1622〜1 626頁、 1 987年） 。 また、 アトピー性喘息患者に対 しアレルゲン吸入を行うと肺胞洗浄液中の iS—トリプ夕ーゼレベルは増大する （ ブスケ （Bou s Q i e t) ら、 ジャーナル、 ォブ、 アレルギー、 アンド、 クリ 二カル、 ィムノロジー （J. A l l e r gy C l i n. I mmu n o 1. ) 、 第 88巻、 649— 660頁、 1991年） など、 これらアレルギー性疾患の病 態部位において ^トリプ夕ーゼの発現増強が認められることが多数報告されてい る。 Tryptase has also been suggested to be associated with disease states. For example, in patients with systemic anaphylactic shock, such as bee algi, the blood iS-triplease content is continuously elevated (Schwartz et al., New, England, Journal, Ob, Medicine (N Engl. J. Med.), Vol. 316, pp. 1622-1626, 1987). In addition, allergen inhalation in patients with atopic asthma increases the level of iS-trypase in the alveolar lavage fluid (Bou s Q iet et al., Journals, ovs, allergies, and cliches). Nikaru, Immunology (J. Allergy Clin. Immu no 1.), Vol. 88, pp. 649-660, 1991). There have been many reports of enhanced expression.
トリプ夕一ゼの生体内基質として p r o t e i n a s e a c t i va t e d r e c ep t o r— 2 (PAR— 2 :プロティナ一ゼ活性化受容体一 2 ) 、 補 体 C3、 VI P (Va s o a c t i ve i n t e s t i n a l p e p t i d e ：血管作用性小腸べプチド） 、 CGRP (c a l c i t on i n gene— r e l a t e d p e t i de :カルシトニン遺伝子関連べプチド） などが報 告されており、 これらのタンパク質切断作用を介して気道収縮、 血管透過 性亢進、 気道上皮細胞や線維芽細胞の活性化などをもたらすことが示唆されてい る。 また、 /3トリプタ一ゼは脱顆粒反応特異的に細胞外へ分泌されること、 細胞 内の顆粒中においてはその生体内阻害因子であり、 塩基性蛋白質であるトリブス 夕チンとともに局在する （勝沼ら、 生化学、 第 62巻、 18〜31頁、 1990 年） ことから、 0 トリプターゼは肥満細胞の脱顆粒反応により特異的に気道 収縮、 気道炎症を惹起し、 肥満細胞が脱顆粒しない限り生体に対して作用しない と思われる。 以上から、 ヒト /3トリプタ一ゼを阻害する物質は、 肥満細胞が関与 する疾患、 とりわけ、 気管支喘息などアレルギー性疾患に対する治療に有用と考 えられている。  Proteinaseacti va ted recep tor-2 (PAR-2: proteinase-activated receptor-1), complement C3, VIP (Va soacti ve intestinal peptide: vasoactive intestinal peptide) ), CGRP (calcit on in gene—related peti de: calcitonin gene-related peptide), etc., have been reported, and through these protein cleavage actions, airway constriction, vascular hyperpermeability, airway epithelial cells and fibroblasts have been reported. It has been suggested that they cause activation. In addition, / 3 tryptase is secreted extracellularly in the degranulation reaction, and is an inhibitor in vivo in the intracellular granule, and is co-localized with the basic protein tribus sutin ( Katsunuma et al., Biochemistry, Vol. 62, pp. 18-31, 1990) Therefore, 0 tryptase specifically causes airway contraction and airway inflammation by mast cell degranulation, and unless mast cells are degranulated. It does not seem to act on living organisms. From the above, it is considered that a substance that inhibits human / 3 tryptase is useful for treating mast cell-related diseases, particularly allergic diseases such as bronchial asthma.
しかし現在までのところ、 1 トリプターゼを抑制する低分子阻害剤は多く報告 されているが、 ヒト /3 トリプタ一ゼを極めて選択的に抑える化合物 (トリプ ターゼ以外のセリンプロテアーゼに対して、 1万倍以上の選択性を有する) は、 明確には知られていない。 また、 低分子化合物において、 ヒト^トリブターゼに 結合し、 選択的に阻害する薬物は医薬品として未だ上市されるまでには至ってい ない。 However, to date, although many small molecule inhibitors that inhibit tryptase have been reported, compounds that extremely selectively inhibit human / 3 tryptase (10,000 times that of serine proteases other than tryptase) have been reported. Has the above selectivity) Not explicitly known. In addition, drugs that bind to human ^ tributase and selectively inhibit low molecular weight compounds have not yet been marketed as pharmaceuticals.
Bod eら （Na t u r e、 第 392巻、 306頁、 1998年、 W099Z 40073号公報） により、 ヒト /3トリプ夕一ゼの結晶構造が解析された。 AP P Aとの複合体結晶の解析により、 ヒト jSトリプタ一ゼの 4量体の三次元構 造が示され、 トリプシンと同様の活性部位近傍の S 1ポケットの位置が、 三次元 構造より示されている。 ヒト 3トリプタ一ゼの活性部位近傍はトリプシンタイプ のセリンプロテアーゼ （トリプシン、 FXa 、 トロンビン、 プラスミン等） に似て いることにより、 生体内において他の薬理作用を発揮するセリンプロテア一ゼを 阻害する可能性が高い。 このような欠点がなくヒト )3トリプ夕一ゼに選択性を有 する薬剤が望まれる。  Bode et al. (Natour, 392, 306, 1998, W099Z 40073) analyzed the crystal structure of human / 3 tryptic enzyme. Analysis of the complex crystal with APPA shows the three-dimensional structure of the tetramer of human jS tryptase, and the location of the S1 pocket near the active site, similar to trypsin, from the three-dimensional structure. ing. The vicinity of the active site of human 3-tryptase is similar to trypsin-type serine proteases (trypsin, FXa, thrombin, plasmin, etc.), which can inhibit serine proteases that exert other pharmacological effects in vivo High. A drug which does not have such a drawback and has selectivity for human 3) trypsinase is desired.
Bod eらは、 上記三次元構造の解析により、 ヒト i3トリプ夕一ゼの阻害剤と して、 二官能性阻害物質の提案をしている。 しかしこの物質は、 トリプターゼ 4 量体の 4つの S 1ポケットのうちの 2つと同時に相互作用しうる阻害物質を目指 したものであるため、 分子量としてはかなり大きい化合物である。  Bode et al. Have proposed a bifunctional inhibitor as an inhibitor of human i3 trypase by analyzing the above three-dimensional structure. However, it is a fairly high molecular weight compound because it is aimed at inhibitors that can interact simultaneously with two of the four S1 pockets of the tryptase tetramer.
またこの化合物の提案以上には、 具体性を持って、 ヒト iSトリプターゼを強力 にかつ、 選択的に阻害し得る情報の特定には至っておらず、 上記の想定化合物と 卜リプターゼとの複合体結晶も取得されておらず、 そのような能力を有する阻害 剤を論理的に探索する手法や、 デザインする手法は知られていなかった。  Further, beyond the proposal of this compound, no information has been identified that can inhibit human iS tryptase strongly and selectively with specificity, and a complex crystal of the above-mentioned putative compound and tryptase has not been identified. No method has been obtained, and there is no known method for logically searching for or designing inhibitors with such capabilities.
また、 Bod eらの方法 （前出 N a t u r e) では、 ヒト )3トリプ夕ーゼの結 晶化に 1年要している。 また同一発明者等による WO 99/40073にも同様 の記載があるが、 結晶化の期間の記載はない。 この B o d eらの方法では、 さら なる阻害剤との複合体の結晶構造の解析により、 新規なヒト /3トリプターゼに選 択性を有する薬剤の探索には長時間を要するという難点が認められる。 発明の開示 According to the method of Bode et al. (Nature, supra), it takes one year to crystallize human 3) trypsinase. The same applies to WO 99/40073 by the same inventors. There is no description of the crystallization period. In the Bode et al. Method, analysis of the crystal structure of the complex with the further inhibitor reveals that it takes a long time to search for a novel human / 3 tryptase-selective drug. Disclosure of the invention
かかる状況下において、 トリプターゼの複合体結晶構造解析を実用的に行うた めの手法、 及び結晶性の良いトリプターゼが望まれる。  Under such circumstances, a technique for practically analyzing the crystal structure of the complex of tryptase and a tryptase having good crystallinity are desired.
さらには、 ヒト トリプターゼを選択的に阻害する低分子化合物を見出すため に、 新規なヒト ι8トリプターゼに選択的な薬剤の探索方法や分子設計方法が望ま れる。  Furthermore, in order to find low-molecular compounds that selectively inhibit human tryptase, a novel drug-selective method for human tryptase and a method for molecular design are desired.
本発明者らは上記課題を解決すべく、 鋭意研究を重ねた結果、 活性を有し結晶 性の良いトリプターゼおよびその製法、 結晶化トリプ夕一ゼを従来よりも早く製 造する方法、 トリプターゼと特定のトリプターゼ活性を阻害する化合物との複合 体結晶、 並びに上記の方法を応用した新規なトリプ夕ーゼ活性を阻害する化合物 のスクリーニング方法を開発した。 またヒト 3 トリプ夕ーゼと特定のヒト 3トリプターゼ活性を阻害する化合物との複合体結晶の構造を解析することによ り、 ヒト )3トリプ夕一ゼ活性を阻害する化合物のフアルマコフォアを見出し、 該 フアルマコフォアを用いるヒト /3トリプ夕ーゼ活性を阻害する化合物のスクリ一 ニング方法、 ドラッグデザイン方法を発明し、 該ドラッグデザイン方法より得ら れたヒト 3トリプ夕一ゼ活性を阻害する化合物のライブラリ一を作成し、 先述の 課題を解決した。  The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have been found to have tryptase having activity and good crystallinity, a method for producing the same, a method for producing crystallized trypticase earlier than before, and tryptase. We have developed a complex crystal with a compound that inhibits a specific tryptase activity, and a novel screening method for a compound that inhibits trypsase activity by applying the above method. In addition, by analyzing the structure of a complex crystal of human 3-trypase and a compound that inhibits a specific human 3-tryptase activity, a pharmacophore of a compound that inhibits human) 3-trippase activity was found. A method for screening a compound inhibiting human / 3-tripse activity using the pharmacophore, a method for designing a drug, and a method for designing a compound inhibiting human 3-tripse activity obtained by the drug designing method are disclosed. A library was created to solve the aforementioned problems.
すなわち、 本発明は、 以下の新規なトリプ夕ーゼ、 その製造方法、 結晶化 トリプ夕一ゼの製造方法、 複合体結晶、 スクリーニング方法、 ドラッグデザイン 方法、 ライブラリー及びフアルマコフオアを提供する。 以下、 本発明の具体例を 挙げる。 That is, the present invention provides the following novel trypase, its production method, crystallization Provided are a method for producing trypticase, a complex crystal, a screening method, a drug design method, a library, and a pharmacophore. Hereinafter, specific examples of the present invention will be described.
(1) 天然トリプターゼまたはリコンビナントトリプ夕一ゼを未変性の状態で糖 鎖切断処理して得られる、 SDS—PAGEでクマシ一染色により単一バンドと して検出されるトリプ夕一ゼ。 すなわち糖鎖が切断され、 実質的に糖鎖を有しな いが、 酵素活性を有する天然トリプ夕一ゼまたはリコンビナント トリプ タ一ゼで、 SDS— PAGEでクマシ一染色により単一バンドとして検出される 卜リプ夕一ゼ。  (1) Trypsinase obtained by subjecting native tryptase or recombinant trypase to carbohydrate cleavage in an undenatured state and detected as a single band by Coomassie staining on SDS-PAGE. That is, the sugar chain is cleaved, and it is detected as a single band by Coomassie staining on SDS-PAGE with natural trypase or recombinant tryptase, which has substantially no sugar chain but has enzymatic activity. Ru Trip Yuichi.
(2) 前記糖鎖切断処理がエンド一 3— N—ァセチルダルコサミニダーゼ (End o— jS— ac e t y l g l uc o s ami n i d a s e) による処理で ある （1) のトリプタ一ゼ。  (2) The tryptase according to (1), wherein the sugar chain cleavage treatment is a treatment with endo-3-N-acetyldarcosaminidase (Endo-jS-acetylglcucosamidnidase).
(3) 糖鎖切断処理する前と比較して酵素活性が 50%以上維持されている (1) のトリプ夕一ゼ。  (3) The trypticase of (1), in which the enzyme activity is maintained at 50% or more as compared with that before the sugar chain cleavage treatment.
(4) SDS— PAGEによる分子量が約 33 kD aである （1) のトリプター ゼ。  (4) The tryptase according to (1), which has a molecular weight of about 33 kDa according to SDS-PAGE.
(5) シッティングドロップ蒸気拡散法にて 2ヶ月以内で結晶化できる （1) の トリプ夕一ゼ。  (5) Tryptic (1), which can be crystallized within 2 months by sitting drop vapor diffusion method.
(6) 天然トリプターゼまたはリコンビナントトリプターゼを、 未変性の状態で 糖鎖切断酵素で処理する工程を含むことを特徴とする、 糖鎖切断処理する前と比 較して酵素活性を 50 %以上維持されている、 糖鎖が実質的に切断されたトリプ ターゼの製造方法。 ( 7 ) 糖鎖切断酵素が、 End o— ]3— a c e t y l g l u c o s ami n i d a s eである （6) の製造方法。 (6) A step of treating native tryptase or recombinant tryptase in a native state with a sugar chain-cleaving enzyme, wherein the enzyme activity is maintained by 50% or more compared to before the sugar chain-cleaving treatment. A method for producing a tryptase having a sugar chain substantially cleaved. (7) The method for producing (6), wherein the sugar chain-cleaving enzyme is Endo—] 3-acetylglucos aminidase.
(8) 糖鎖切断酵素で処理する工程において、 キレート剤存在下、 ΡΗ5· 0〜 ΡΗ7. 0の緩衝液中で 30〜40°Cの条件で、 糖鎖切断酵素で処理することを 特徴とする工程である （6) の製造方法。  (8) In the step of treating with a sugar chain-cleaving enzyme, the treatment with the sugar chain-cleaving enzyme is carried out in the presence of a chelating agent at a temperature of 30 to 40 ° C in a buffer of ΡΗ5.0 to · 7.0. (6).
(9) 天然トリプターゼまたはリコンビナントトリプターゼを、 未変性の状態で 糖鎖切断酵素で処理して、 結晶化することを特徴とするトリプターゼ結晶の製造 方法。  (9) A method for producing a tryptase crystal, comprising treating native tryptase or recombinant tryptase in a native state with a sugar chain-cleaving enzyme to crystallize the same.
(10) 天然トリプ夕ーゼまたはリコンビナントトリプ夕ーゼを、 未変性の状態 で糖鎖切断酵素で処理した後、 天然トリプ夕一ゼまたはリコンビナント トリプタ一ゼとァフィ二ティを持つ物質との複合体を作成し、 結晶化することを 特徴とするトリプタ一ゼと、 当該物質との複合体結晶の製造方法。  (10) After treating native trypase or recombinant trypase with a glycolytic enzyme in a native state, complexing the natural trypase or recombinant tryptase with a substance having affinity A method for producing a composite crystal of a tryptase and a substance, wherein the substance is prepared and crystallized.
(11) 前記結晶化において、 ポリオールを沈殿剤に用いるシッティング ドロップ蒸気拡散法により、 結晶化することを特徴とする （9) または （10) の結晶の製造方法。  (11) The method for producing crystals according to (9) or (10), wherein the crystallization is carried out by a sitting drop vapor diffusion method using a polyol as a precipitant.
(12) (1) のトリプ夕ーゼと、 該トリブターゼにァフィニティを有する物質 との複合体結晶。  (12) A composite crystal of the trypase of (1) and a substance having an affinity for the tryptase.
(13) トリプターゼと、 N— [2— [N— [3 - [4 - (アミノメチル) フエニル] プロピル] ァミノ] ェチル] 一 2—ナフタレンスルホンアミドまたは その塩との複合体結晶。  (13) Complex crystals of tryptase and N— [2-—N— [3- [4- (aminomethyl) phenyl] propyl] amino] ethyl] -1-naphthalenesulfonamide or a salt thereof.
(14) トリプ夕ーゼと、 N— [2- [N- [3— [4— (アミノメチル） フエ ニル] プロピル] —N—メチリレアミノ] ェチル] —2—べンゾ [b] チォフェン 力ルポキサミドまたはその塩との複合体結晶。 (14) Trypase and N- [2- [N- [3- [4- (aminomethyl) phenyl] propyl] —N-methylylamino] ethyl] —2-benzo [b] thiophene Complex crystals with lipoxoxamide or a salt thereof.
( 1 5 ) 以下の工程を含むことを特徴とするトリプターゼ活性を阻害する化合物 のスクリーニング方法  (15) A method for screening for a compound that inhibits tryptase activity, comprising:
①糖鎖切断したトリプ夕ーゼとあらかじめトリプタ一ゼ活性を阻害すること がわかっている化合物との複合体結晶を作成する工程  (1) A process for preparing a complex crystal of a glycosylated tripsease and a compound that is known to inhibit tryptase activity in advance
②前記作成した結晶の構造を解析し、 糖鎖切断したトリプ夕一ゼと前記化合 物との相互作用から、 トリプターゼ活性を阻害する化合物のフアルマコフォアを 作成し、 トリプターゼ活性を阻害する化合物をバーチャルで選択する工程  (2) Analyze the structure of the crystal prepared above, and create a pharmacophore of a compound that inhibits tryptase activity from the interaction between the sugar chain-cleaved trypticase and the compound. Process to select
③前記 一チャルで選択した化合物をリアルで用意する工程、 及び ④用意した前記化合物のトリプターゼ活性に対する影響を in v i t roの系 および Zまたは in vivo の系にて測定する工程。  (3) a step of preparing the compound selected in the above-mentioned manner in real time; and (4) a step of measuring the effect of the prepared compound on the tryptase activity in an in vitro system and a Z or in vivo system.
( 1 6 ) 前記②のトリプターゼ活性を阻害する化合物をバーチャルで選択するェ 程が、 前記フアルマコフォアをコンピューターソフトウエアに供用することによ り、 当該フアルマコフォアを満たすトリプタ一ゼ活性を阻害する化合物を バーチャルで選択する工程である （1 5 ) に記載のスクリーニング方法。  (16) The step of virtually selecting the compound that inhibits the tryptase activity in the step (ii) is performed by applying the pharmacophore to computer software to virtually convert the compound that inhibits the tryptase activity that satisfies the pharmacophore. (15) The screening method according to (15), which is a step of selecting.
( 1 7 ) 後述する表 1に記載の条件 1〜4をすベて満たすフアルマコフォア をコンピューターソフトウェアに供用することにより、 当該フアルマコフォアを 満たすヒト i3トリプタ一ゼ活性を阻害する化合物をバーチャルで選択する工程を 含むことを特徴とする、 ヒト /3 トリプターゼ活性を選択的に阻害する化合物 のスクリーニング方法。  (17) A step of virtually selecting a compound that inhibits human i3 tryptase activity that satisfies the pharmacophore by applying the pharmacophore that satisfies all of the conditions 1 to 4 described in Table 1 below to computer software. A method for screening a compound that selectively inhibits human / 3 tryptase activity, comprising:
( 1 8 ) 後述する表 2に記載の条件 1〜4をすベて満たすフアルマコフォア をコンピューターソフトウエアに供用することにより、 当該フアルマコフォアを 満たすヒト 0トリプターゼ活性を阻害する化合物をバーチャルで選択する工程を 含むことを特徴とする、 ヒト /3 トリプターゼ活性を選択的に阻害する化合物 のスクリーニング方法。 (18) A pharmacophore that satisfies all of the conditions 1 to 4 described in Table 2 described below is supplied to computer software, so that the pharmacophore is A method for screening a compound that selectively inhibits human / 3 tryptase activity, comprising a step of virtually selecting a compound that inhibits human 0 tryptase activity.
( 1 9 ) さらに以下の工程を含むことを特徴とする （1 7 ) または （1 8 ) のヒト ]3トリプタ一ゼ活性を選択的に阻害する化合物のスクリーニング方法 (19) A method for screening a compound that selectively inhibits the human] 3 tryptase activity of (17) or (18), further comprising the following steps:
②前記バーチャルで選択した化合物をリアルで用意する工程、 及び(2) a process of preparing the virtual selected compound in real; and
③前記用意した化合物のトリプ夕ーゼ活性に対する影響を in vi t roの系 および/または in vivo の系にて測定する工程。 (3) a step of measuring the effect of the compound prepared above on trypsinase activity using an in vitro system and / or an in vivo system.
( 2 0 ) 以下の工程を含むことを特徴とするヒト /3トリプターゼ活性を選択的に 阻害する化合物のドラッグデザィン方法  (20) A drug design method for a compound that selectively inhibits human / 3 tryptase activity, comprising the following steps:
①後述する表 1に記載のフアルマコフオアの各条件に対応する官能基を有す る各フラグメント群を作成する工程。  (1) A step of preparing each fragment group having a functional group corresponding to each condition of the pharmacophore described in Table 1 described below.
②①で作成した各フラグメント群より一つずつ選択された各フラグメントを 結合させて、 化合物をモデル構築する工程。  (2) A process in which each fragment selected from each fragment group created in (1) is combined to construct a compound model.
( 2 1 ) 以下の工程を含むことを特徴とするヒト 0トリプ夕一ゼ活性を選択的に 阻害する化合物のドラッグデザィン方法  (21) A drug design method for a compound that selectively inhibits human 0-trypticase activity, comprising the following steps:
①後述する表 2に記載のフアルマコフオアの各条件に対応する官能基を有す る各フラグメント群を作成する工程。  (1) A process of preparing each fragment group having a functional group corresponding to each condition of the pharmacophore described in Table 2 described below.
②①で作成した各フラグメント群より一つずつ選択された各フラグメントを 結合させて、 化合物をモデル構築する工程。  (2) A process in which each fragment selected from each fragment group created in (1) is combined to construct a compound model.
( 2 2 ) ヒト ]3トリプ夕ーゼ活性を選択的に潜在的に阻害しうる化合物からなる 化合物アレイの作成方法であり、 後述する表 1に記載のフアルマコフォアを コンピュータ一ソフトウェアに供用することにより前記フアルマコフォアを満た すヒト; 6トリプターゼ活性を選択的に阻害する化合物をバーチャルで選択し、 選 択した化合物をリアルで用意して組み合わせて、 化合物ァレイを作成する 方法。 (22) Human] 3 is a method for preparing a compound array consisting of compounds capable of selectively inhibiting trypsinase activity, wherein the pharmacophore described in Table 1 below is prepared. A human who satisfies the pharmacophore by applying it to a computer software; 6 A method of virtually selecting a compound that selectively inhibits tryptase activity, preparing the selected compounds in real time, and combining them to form a compound array .
(2 3) ヒト ]3トリプターゼ活性を選択的に潜在的に阻害しうる化合物アレイの 作成方法であり、 後述する表 2に記載のフアルマコフォアをコンピュータ一 ソフトウエアに供用することにより前記フアルマコフォアを満たすヒト 3トリプ 夕ーゼ活性を選択的に阻害する化合物をバーチャルで選択し、 選択した化合物を リアルで用意して組み合わせて、 化合物ァレイを作成する方法。  (2 3) Human) A method for preparing a compound array capable of selectively and potentially inhibiting a tryptase activity, wherein a human who satisfies the pharmacophore by applying the pharmacophore described in Table 2 below to computer software. (3) A method in which compounds that selectively inhibit tripase activity are virtually selected, and the selected compounds are prepared in real time and combined to create a compound array.
(24) 後述する表 3および表 4に記載のフラグメント群より構築した 一般式 Si — L一 A rの化合物のデータベースを、 後述する表 1または表 2に示 すフアルマコフォアをコンピュータ一ソフトウエアに供用することにより選択さ れる、 ヒト ]3トリプ夕ーゼ活性を選択的に潜在的に阻害しうる化合物のライブラ' リー。  (24) The database of compounds of the general formula Si—L-Ar constructed from the fragment groups described in Tables 3 and 4 described below is used for computer-software using the pharmacophore shown in Tables 1 and 2 described below. A library of compounds that can selectively and potentially inhibit human] 3 tripsease activity.
(2 5) 後述する表 1に示すフアルマコフォア  (25) The pharmacophore shown in Table 1 below
(2 6) 後述する表 2に示すフアルマコフォア  (26) The pharmacophore shown in Table 2 below
(2 7) 後述する表 1または表 2に記載されるフアルマコフオアを満たすヒト β トリプ夕ーゼ活性を阻害する下記のいずれかの化合物若しくはその薬理学的に許 容される塩。  (27) Any one of the following compounds or a pharmacologically acceptable salt thereof, which inhibits human β-trippase activity that satisfies the pharmacophore described in Table 1 or Table 2 described below.
Ν- [1— [4- (アミノメチル） フエニル] ピぺリジン一 4—ィル] — Ν— [ 1一 [4一 (アミノメチル) フエニル] ピぺリジン一 4—ィルメチル] ァセト アミド、 ビス [3— [4- (アミノメチル) フエニル] プロピル一 (2—アミノエチル ) ァミン、 Ν- [1 -— [4- (Aminomethyl) phenyl] piperidin-1-yl] — Ν— [1-1- [4-1 (aminomethyl) phenyl] piperidin-1-4-ylmethyl] acetamide, Bis [3- [4- (aminomethyl) phenyl] propyl- (2-aminoethyl) amine;
N— [2 - [N— [2- [4 - (アミノメチル） フエノキシ] ェチル] ァミノ] ェチル] 一 2—ナフ夕レンスルホンアミド、  N— [2-[N— [2- [4- (aminomethyl) phenoxy] ethyl] amino] ethyl] -1-naphthenelensulfonamide,
N- [2— [N- [3— [4一 (アミノメチル) フエニル] プロパノィル] 一 N—メチルァミノ] ェチル] —2—べンゾ [b] チォフェンカルポキサミド、 N- [2 -— [N- [3 -— [4- (Aminomethyl) phenyl] propanoyl] -1-N-methylamino] ethyl] —2-benzo [b] thiophencarpoxamide,
N— ( 4ーピペラジニルフエニル) — [ 1— (4一フエニル) ベンゼンスルホ 二ルー 4ーピペリジン] カルポキサミド、 N— (4-Piperazinylphenyl) — [1- (4-Phenyl) benzenesulfo-2-ru 4-piperidine] carpoxamide,
N— [1— （4一フエエル） ベンゼンスルホニル一 4ーピペリジル] 一 （4— グァニジノベンゼン） カルボキサミド、  N— [1— (4-phenyl) benzenesulfonyl-1-4-piperidyl] -1- (4-guanidinobenzene) carboxamide,
N- [2- [N- [3- [4- (アミノメチル) フエニル] プロピル] -N- メチルァミノ] ェチル] —2, 3—ナフタレンジカルポキシミド、 若しくは  N- [2- [N- [3- [4- (aminomethyl) phenyl] propyl] -N-methylamino] ethyl] —2,3-naphthalenedicarboximide or
C 1一 [4- (アミノメチル) フエニル] ピぺリジン一 4—ィル] 一 [1— [ 4一 (アミノメチル) フエニル] ピぺリジン一 4一ィルメチル] ェチルァミン。 図面の簡単な説明  C1- [4- (Aminomethyl) phenyl] piperidine-1-yl] 1- [1- [4- (Aminomethyl) phenyl] piperidine-14-ylmethyl] ethylamine. BRIEF DESCRIPTION OF THE FIGURES
図 1は、 糖鎖切断酵素 （酵素番号 3. 2. 1. 96に属する酵素） En do - β— Ν— a c e t y l g l uc o s ami n i d a s eの糖鎖切断部位の図で ある。  FIG. 1 is a diagram of a sugar chain cleavage site of a sugar chain cleavage enzyme (enzyme belonging to the enzyme number 3.2.1.96) Endo-β-Ν—acetylglgucosamidnidase.
図 2は、 本発明のスクリーニングの例を示したフローチャート図である。  FIG. 2 is a flowchart showing an example of the screening of the present invention.
図 3は、 糖鎖切断したトリプ夕一ゼの精製過程を、 それぞれ SDS— PAGE で電気泳動した図である。 図 4は、 X線回折実験の結果、 三次元構造解析から獰られたヒト ]3 トリプ 夕一ゼ 4量体と化合物 A 4分子の複合体のリポン図である。 A、 B、 C及び Dは 卜リプターゼの各分子を示す。 Figure 3 shows the results of electrophoresis by SDS-PAGE of the purification process of trypsinase with sugar chains cleaved. FIG. 4 is a Ripon diagram of a complex of a human] 3 trypase tetramer and four molecules of compound A, which was terrified by three-dimensional structural analysis as a result of X-ray diffraction experiment. A, B, C and D represent each molecule of tryptase.
図 5は、 X線回折実験の結果、 三次元構造解析から得られたヒト; S卜リブター ゼ 2分子と化合物 A 2分子の複合体のリボン図であり、 図 4の卜リブターゼ 4量 体の A及び D分子について、 4量体の中心側から見た図である。  FIG. 5 is a ribbon diagram of a complex of two molecules of human S-tribase and two molecules of compound A obtained from three-dimensional structural analysis as a result of an X-ray diffraction experiment. FIG. 3 is a view of A and D molecules as viewed from the center of a tetramer.
図 6は、 X線回折実験の結果、 三次元構造解析から得られたヒト |3トリプター ゼ 4量体と化合物 B 4分子の複合体のリポン図である。 A、 B、 C及び Dはトリ プターゼの各分子を示す。  FIG. 6 is a Ripon diagram of a complex of human | 3 tryptase tetramer and four molecules of compound B obtained from three-dimensional structural analysis as a result of an X-ray diffraction experiment. A, B, C and D represent each molecule of tryptase.
図 7は、 X線回折実験の結果、 三次元構造解析から得られたヒト トリプタ一 ゼ 2分子と化合物 A 2分子の複合体のリボン図であり、 図 6のトリプターゼ 4量 体の A及び D分子について、 4量体の中心側から見た図である。  FIG. 7 is a ribbon diagram of a complex of two molecules of human tryptase and two molecules of compound A obtained from the three-dimensional structure analysis as a result of the X-ray diffraction experiment.A and D of the tryptase tetramer in FIG. 6 are shown. FIG. 3 is a diagram of a molecule as viewed from the center of a tetramer.
図 8は、 ヒト /3トリプターゼの化合物 Aの結合部位を示す図であり、 図 4 のトリプターゼ 4量体の A及び D分子についての図である。  FIG. 8 is a diagram showing the binding site of compound A of human / 3 tryptase, and is a diagram of the A and D molecules of the tryptase tetramer in FIG.
図 9は、 ヒト 3トリプターゼと化合物 A複合体の結合部位を示す図であり、 図 4のトリプ夕ーゼ 4量体の A及び D分子についての図である。  FIG. 9 is a diagram showing a binding site between human 3 tryptase and a compound A complex, and is a diagram showing the A and D molecules of the trypase tetramer in FIG.
図 1 0は、 表 1に示すフアルマコフォアの模式図である。 化合物の官能基は籠 状の球で示す。 網掛けの部分は隣接する卜リプターゼ分子を示す。  FIG. 10 is a schematic diagram of the pharmacophore shown in Table 1. The functional groups of the compounds are indicated by basket-shaped spheres. Shaded cells indicate adjacent tryptase molecules.
図 1 1は、 ヒト /3トリプターゼの化合物 Bの結合部位を示す図であり、 図 6の トリプ夕ーゼ 4量体の A及び D分子についての図である。  FIG. 11 is a diagram showing the binding site of compound B of human / 3 tryptase, and is a diagram of the trypase tetramer A and D molecules of FIG.
図 1 2は、 ヒト |3トリプ夕一ゼと化合物 A複合体の結合部位を示す図であり、 図 6のトリプ夕ーゼ 4量体の A及び D分子についての図である。 図 13は、 表 2に示すフアルマコフォアの模式図である。 化合物の官能基は籠 状の球で示す。 化合物、 トリプターゼ分子はそれぞれ 2分子分示す。 FIG. 12 is a diagram showing the binding site between the human | 3 trypase and the compound A complex, and is a diagram showing the A and D molecules of the trypase tetramer in FIG. FIG. 13 is a schematic diagram of the pharmacophore shown in Table 2. The functional groups of the compounds are indicated by basket-shaped spheres. The compound and the tryptase molecule represent two molecules each.
図 14は、 実施例 7 (2) 一 1で使用した特性球の模式図である。 （A) は化 合物 Aをべ一スとして記載した図である。 （B) は、 各特性球の中心間の距離を 示す図である。 （C) は、 各特性球の中心間を線で結んだ場合に得られる角度を 示す図である。  FIG. 14 is a schematic diagram of the characteristic sphere used in Example 7 (2) -11. (A) is a diagram in which compound A is described as a base. (B) is a diagram showing the distance between the centers of the characteristic spheres. (C) is a diagram showing angles obtained when lines between the centers of the characteristic spheres are connected.
図 15は、 実施例 7 (2) 一 2で使用した特性球の模式図である。. (A) は化 合物 Bをベースとして記載した図である。 （B) は、 各特性球の中心間の距離を 示す図である。 （C) は、 各特性球の中心間を線で結んだ場合に得られる角度を 示す図である。  FIG. 15 is a schematic diagram of the characteristic sphere used in Example 7 (2) -12. (A) is a diagram based on Compound B. (B) is a diagram showing the distance between the centers of the characteristic spheres. (C) is a diagram showing angles obtained when lines between the centers of the characteristic spheres are connected.
図 16は、 実施例 7 (2) _ 3で使用した特性球の模式図である。 （A) は化 合物 Bをベースとして記載した図である。 （B) は、 各特性球の中心間の距離を 示す図である。 （C) は、 各特性球の中心間を線で結んだ場合に得られる角度を 示す図である。 発明を実施するための最良の形態  FIG. 16 is a schematic diagram of the characteristic sphere used in Example 7 (2) _3. (A) is a diagram based on Compound B. (B) is a diagram showing the distance between the centers of the characteristic spheres. (C) is a diagram showing angles obtained when lines between the centers of the characteristic spheres are connected. BEST MODE FOR CARRYING OUT THE INVENTION
以下に、 本発明をより詳細に説明する。  Hereinafter, the present invention will be described in more detail.
本発明の第一の態様は、 実質的に糖鎖がなく、 実質的に均一で、 しかもトリプ ターゼ活性を維持しているトリプターゼである。 具体的には、 天然トリプ夕一ゼ 若しくはリコンビナントトリプターゼを未変性の状態で糖鎖を切断する処理をし て得られる、 SDS— PAGEでクマシ一染色により単一バンドとして検出され る卜リプ夕一ゼである。 「未変性」 とは、 トリプタ一ゼの立体構造が生体内に存在する状態に保たれて おり、 酵素活性が維持されている状態を言う。 加熱、 強塩酸溶液、 強アルカリ溶 液、 Sod i um dod e cy l s u l f a t e (SDS) 、 尿素、 グァニ ジン塩酸などの夕ンパク質変性剤、 2— Me r c ap t o e t h ano l (2— ME) や D i t h i o t h r e i t o l (DTT) などの還元剤による処理をし たトリプタ一ゼは未変性状態とは言わない。 すなわち、 「未変性のまま糖鎖を切 断する処置をする」 とは加熱、 強塩酸溶液、 強アルカリ溶液、 SDS、 尿素、 グ ァニジン塩酸などのタンパク質変性剤、 2—1^£ゃ0丁丁などの還元剤による処 理を行わず、 糖鎖を切断処置することを言う。 好ましくは糖鎖切断酵素の作用だ けで糖鎖を処理することをいう。 A first aspect of the present invention is a tryptase that is substantially free of sugar chains, substantially uniform, and maintains tryptase activity. Specifically, SDS-PAGE can be used to detect native trypsinase or recombinant tryptase by cleaving the sugar chain in a native state, and can be detected as a single band by Coomassie staining. It is ze. The term “native” refers to a state in which the three-dimensional structure of tryptase is maintained in a living body and the enzyme activity is maintained. Heating, strong hydrochloric acid solution, strong alkaline solution, sodium um dod e cylsulfate (SDS), urea, guanidine hydrochloride and other protein denaturants, 2-mercaptoethanol (2-ME) and D Tryptase treated with a reducing agent such as ithiothreitol (DTT) is not said to be in its native state. In other words, "treating the sugar chain without denaturing" means heating, strong hydrochloric acid solution, strong alkaline solution, protein denaturant such as SDS, urea, guanidine hydrochloride, etc. This refers to the treatment of cutting the sugar chain without performing treatment with a reducing agent. Preferably, it refers to treating a sugar chain only by the action of a sugar chain cleavage enzyme.
本発明のトリプタ一ゼは、 天然トリプタ一ゼ若しくはリコンビナント トリプターゼを未変性の状態で糖鎖切断処理して得られる、 SDS— PAGEで クマシ一染色により単一バンドとして検出されるトリプターゼであれば、 糖鎖切 断処理するトリプ夕一ゼ （以降、 処理前トリプターゼと記載） に特に限定は ない。  The tryptase of the present invention is a tryptase which is obtained by subjecting a natural tryptase or a recombinant tryptase to a sugar chain cleavage treatment in a native state, and which can be detected as a single band by Coomassie staining on SDS-PAGE, There is no particular limitation on the type of trypsinase to be subjected to sugar chain cleavage (hereinafter referred to as pre-treatment tryptase).
ひ、 β、 τ、 εといった分子種のトリプターゼが含まれる。 ひ、 ]3トリプ夕ー ゼは生理的条件において 4量体を形成して活性を発現するが、 ァ、 ' εは 4量体を 形成しないと考えられている。 rトリプターゼは t r an smei¾b r ane トリプ夕ーゼ （TMT) とも呼ばれ、 ペプチド C末端部位に疎水性領域があり、 この部分が細胞膜に埋め込まれていると考えられている。 α、 βヽ ァ、 εのどの 分子種にも Νグリコシド結合サイトが 1または 2箇所存在するので、 これらの天 然のトリプターゼまたはリコンビナン卜で作成されたトリプ夕ーゼは糖鎖が付加 している。 処理前トリプターゼにはこれらいずれの卜リプターゼも含まれる。 ヒトの生体内には肺、 皮膚、 消化管、 眼球、 鼻等にトリプタ一ゼが存在してお り、 処理前トリプ夕一ゼとしてはいずれのトリプ夕ーゼも利用可能である。 例え ば肺に存在するトリプ夕ーゼからの Sm i t h等の方法 （Th e J o u r n a 1 o f B i o l og i c a l Ch emi s t ry vo l . 259And tryptase of molecular species such as β, τ, and ε. In addition, [3] trypsinase forms a tetramer under physiological conditions and expresses its activity, but a, 'ε is not considered to form a tetramer. r-tryptase is also called trans-me trypase (TMT), which has a hydrophobic region at the C-terminal part of the peptide, which is thought to be embedded in the cell membrane. Since there are one or two Ν glycoside binding sites in all α, β ァ, and ε molecular species, trypsinase made with these natural tryptases or recombinants has sugar chains added. are doing. The tryptase before treatment includes any of these tryptases. In the human body, tryptase is present in the lung, skin, gastrointestinal tract, eyeball, nose, etc. Any trypase can be used as a pre-treatment trypase. For example, the method of Smith et al. From trypsinase present in the lung (The Journal of Biochemical Chemistry vol. 259)
PP 1 1045— 1 1051 (1984) ) により、 精製して得たトリプタ一 ゼを処理前トリプタ一ゼとして用いてもよい。 According to PP 1 1045-11051 (1984)), a tryptase obtained by purification may be used as a pre-treatment tryptase.
また、 ヒト以外の動物にもトリプ夕一ゼが見出されており、 ィヌ、 マウ ス、 ラット、 スナネズミ、 モルモット、 ゥシ、 ブ夕等の動物に存在しており、 い ずれのトリプタ一ゼも利用可能である。 例えば、 モルモットトリプターゼを肺か ら採取し、 部分精製若しくは精製した卜リプタ一ゼを処理前トリプターゼとして 用いてもよい。  In addition, trypsinase has been found in animals other than humans, and it is present in animals such as dogs, mice, rats, gerbils, guinea pigs, horsetails, and bush. Ze is also available. For example, guinea pig tryptase may be collected from the lung, and partially purified or purified tryptase may be used as pre-treatment tryptase.
リコンビナントトリプターゼは、 H e d y C h a n等の方法 （P r o t e i n Exp r e s s i on and Pu r i f i c a t i on Vo l . 15 251— 257 (1999) ) により、 作成することができる。 また、 巿 販品のリコンビナントヒト iS卜リブターゼ (P r ome g a社、 r h- iS I—ト リブターゼ） 等を用いてもよい。  Recombinant tryptase can be produced by a method such as HedyChan (ProteinExpression and PurificationVol. 15 251-257 (1999)). Alternatively, a commercially available recombinant human iS tributase (Promega, rh-iS I-tributase) may be used.
好ましくは、 ヒトトリプターゼである。 より好ましくはヒト /3トリプ夕一ゼで ある。 また好ましくはリコンビナントトリプ夕ーゼである。 特に好ましくは リコンビナントヒト i3トリプターゼである。  Preferably, it is human tryptase. More preferably, it is human / 3 trypsinase. Also preferred is recombinant trypase. Particularly preferred is recombinant human i3 tryptase.
また、 本発明のトリプ夕一ゼを得るための 「糖鎖切断処理」 は、 「SDS 一 PAGEでクマシ一染色により単一バンドとして検出されるトリプ夕一ゼ」 を 得る処理であれば、 特に限定はない。 例えば、 天然トリプ夕一ゼ若しくはリコン ピナントトリプタ一ゼを未変性のまま以下に説明する糖鎖切断酵素による、 糖鎖 切断処理を用いてもよい。 In addition, the "sugar chain cleavage treatment" for obtaining the trypticase of the present invention includes "a trypticase which is detected as a single band by Kumashii staining on SDS-PAGE". There is no particular limitation as long as the processing can be obtained. For example, a sugar chain cleavage treatment using a sugar chain cleavage enzyme described below may be used without denaturing the natural tryptic enzyme or recombinant tryptase.
糖鎖切断酵素は、 酵素番号 3. 2. 1. 96に属する酵素 End o— /3— N - a c e t y l g l u c o s am i n i d a s eが、使用できる。 例えは、 Endo F l、 Endo F2、 Endo D、 Endo Hが含まれる。  As the sugar chain-cleaving enzyme, an enzyme belonging to the enzyme number 3.2.1.96, Endo— / 3—N-acetylgluccosaminidinase, can be used. For example, Endo F1, Endo F2, Endo D, and Endo H are included.
End o_/6— N— a c e t y l g l u c o s am i n i d a s eの糖鎖切断 部位は N—ァセチルキトビオース結合である （Yamamo t o, K. e t a 1. , J. Fe rme n t. Te c hno 1. ， 64， 397 (1986) ) 。 図 1は、 該糖鎖切断部位を示した図である。  End o_ / 6— The sugar chain cleavage site of N-acetylglucos am inidase is N-acetylchitobiose bond (Yamamo to, K. eta 1., J. Fermentt. Te chno 1., 64 , 397 (1986)). FIG. 1 is a diagram showing the sugar chain cleavage site.
基質側にハイマンノース型またはハイプリッド型糖鎖が存在していれば End o— iS— N— a c e t y 1 g 1 u c o s ami n i d a s eにより、 その 糖鎖切断部位が切断される。 処理前トリプターゼはハイマンノース型またはハイ ブリツド型糖鎖の N—ァセチルキトビオース結合が存在しているので、 Endo 一 ]3— N— a c e t y l g l uc o s ami n i d a s eにより処理することに より糖鎖が切断でき、 SDS— PAGEでクマシー染色により単一バンドとして 検出されるトリプ夕ーゼを得ることができる。  If a high-mannose-type or a hybrid-type sugar chain is present on the substrate side, the sugar chain cleavage site is cleaved by Endo-iS-N-accety1g1ucosaminamidase. Because pre-treatment tryptase has an N-acetyl-chitobiose bond of a high-mannose or hybrid-type sugar chain, the sugar chain can be reduced by treatment with Endo-1] 3-N-acetylglucose ami nidase. Trypsinase can be obtained which can be cleaved and detected as a single band by Coomassie staining on SDS-PAGE.
例えば、 ヒト i3 トリプ夕一ゼの場合、 2 0 3番目のァスパラギン （前出 WO 99 / 60 1 39号公報の配列番号 6参照） に糖鎖が付加されており、 En d o— jS _N— a c e t y l g l u c o s am i n i d a s eで切断 すると、 203番目のァスパラギンに N—ァセチルダルコサミンが付加した形の ヒ卜； 9トリプターゼが得られる。 すなわち、 本明細書では 「糖鎖切断処理」 とは上記の切断を示す。 また、 「糖 鎖が実質的に切断された」 、 「実質的に糖鎖がない」 とは、 ァスパラギン残基にFor example, in the case of human i3 trypticase, a sugar chain is added to the asparagine at position 203 (see SEQ ID NO: 6 in WO 99/60139, supra), and Endo—jS_N—acetylglucos Cleavage with am inidase yields 9-tryptase, a human in the form of asparagine at position 203 plus N-acetyldarcosamine. That is, in the present specification, “sugar chain cleavage treatment” refers to the above cleavage. Also, “substantially the sugar chain is cut” or “substantially no sugar chain” means that the asparagine residue
N—ァセチルダルコサミンが付加された状態を含む。 Includes the state where N-acetyldarcosamine is added.
本発明のトリプターゼを得るための処理前トリプターゼを糖鎖切断酵素で処理 する条件は、 特に限定されない。  Conditions for treating the pre-treated tryptase with the sugar chain-cleaving enzyme to obtain the tryptase of the present invention are not particularly limited.
例えば、 pH5. 0-7. 0の条件で行うことが好ましい。 より好ましくは p H 5. 0-6. 0の条件である。 温度は 25 °C— 50°Cで行うことが好ましい。 より好ましくは、 30°C— 40° (：、 特に好ましくは 37°Cである。 その他の条件 も用いる糖鎖切断酵素の至適条件付近で行うことが好ましい （Agric Biol Che 1990 J an;54(l) :97-106 ) 。  For example, it is preferable to carry out under the condition of pH 5.0-7.0. More preferably, the condition is pH 5.0-6.0. The temperature is preferably from 25 ° C to 50 ° C. More preferably, the temperature is 30 ° C. to 40 ° (:, particularly preferably 37 ° C. It is preferable to carry out the reaction near the optimum conditions of the sugar chain-cleaving enzyme using other conditions (Agric Biol Che 1990 Jan; 54 (l): 97-106).
例えば処理前トリプタ一ゼ 100 g/m 1と End 0— /3— N—a c e t y l g l u c o s ami n i d a s e 65 mU/m 1 ¾適当な十レート斉 U存在 下 pH5. 0の緩衝液中で 37 X：で 4時間以上反応させることにより本発明のト リプタ一ゼを得ることができる。 E n d〇一 ]3 -N- ac e t y l g l uc o s am i n i d a s e 16mU/m 1の場合は、 24時間以上で反応させればよ い。 適当なキレート剤とは、 例えば EDTA 2mM等が挙げられる。  For example, tryptase 100 g / m 1 and End 0- / 3-N-acetylglucos amine 65 mU / m 1 before treatment 37 X: in the buffer of pH 5.0 in the presence of an appropriate amount of U The reaction of the present invention can be carried out for more than an hour to obtain the present protease. En d〇1] 3 -N- ac e t y l g l uc o s am i n i d a s e In the case of 16 mU / m1, the reaction may be performed in 24 hours or more. Suitable chelating agents include, for example, 2 mM EDTA.
この様にして得られた本発明のトリプターゼは、 ゲルろ過カラム、 イオン交換 カラム、 へパリンァガロースカラム、 HP LC等の通常の精製方法を用いて、 精 製することができる。 また、 限外ろ過、 カラム濃縮等の通常の濃縮方法を用 いて、 濃縮することができる。  The tryptase of the present invention thus obtained can be purified using a conventional purification method such as a gel filtration column, an ion exchange column, a heparin agarose column, and an HP LC. Further, the concentration can be carried out by using a usual concentration method such as ultrafiltration or column concentration.
本発明のトリプターゼは、 SDS— PAGEでクマシ一染色により、 単一バン ドとして検出される。 これは糖鎖切断前のトリプターゼが糖鎖切断処理されて、 実質的に糖鎖がないトリプ夕ーゼとなり、 実質的に均一と成るためである。 処理前トリプ夕一ゼとして、 ヒト 13トリプタ一ゼを用いる場合は、 SDS— P AGEにより分子量が約 33 kD aとして検出される。 The tryptase of the present invention is detected as a single band by coomassie staining on SDS-PAGE. This is because tryptase before sugar chain cleavage is subjected to sugar chain cleavage treatment, This is because it becomes a trypsinase having substantially no sugar chains and is substantially uniform. When human 13 tryptase is used as the pre-treatment trypase, the molecular weight is detected as about 33 kDa by SDS-PAGE.
本発明のトリプタ一ゼは、 糖鎖切断処理前のトリプターゼ活性を維持する。 た だし、 処理前トリプタ一ゼと酵素活性の強度が異なっていてもよい。 糖鎖切断後 のトリプタ一ゼの精製度や処理前トリプターゼの精製度等により酵素活性すなわ ち比活性は異なるからである。 好ましくは処理前トリプターゼと比較して酵素活 性が 50 %以上維持されているトリプターゼである。 より好ましくは 70 % 以上、 さらに好ましくは 80%以上維持されているトリプターゼである。 また処 理前トリプターゼと比較して酵素活性が 100%を超えていても構わなく、 好ま しい。  The tryptase of the present invention maintains the tryptase activity before the sugar chain cleavage treatment. However, the intensity of the enzyme activity may be different from that of the pre-treatment tryptase. This is because the enzymatic activity, that is, the specific activity, differs depending on the degree of purification of tryptase after sugar chain cleavage and the degree of purification of tryptase before treatment. Preferably, it is a tryptase in which the enzyme activity is maintained at 50% or more as compared with the tryptase before the treatment. It is more preferably 70% or more, and still more preferably 80% or more. In addition, the enzyme activity may be more than 100% as compared with the tryptase before the treatment, and is preferable.
トリブターゼの活性測定方法は特に限定されない。 S c hwa r t zらの方法 (The J ou r na l o f B i o l og i c a l Chem i s t ry 256巻 11939頁） 、 Sm i t hらの方法 （Th e J ou rn a l o f B i o l og i c a l Ch emi s t ry 259卷 1 1046頁 1984年） 、 Comb r i nkらの方法 （J ou r n a l o f Me d i c a 1 Ch emi s t ry 41巻 4854頁 1998年） 、 Ka t zらの 方法 （Na t u r e 391巻 608頁 1998年） 、 Cau ghyらの方 法 、 t he J ou rn a l o f Ph a rma c o 1 ogyExp e r im e n t a l The r ap e u t i c s 264卷 676頁） 、 Wa l l sら の方法 （The J ou r n a l o f Immuno l ogy 6217頁 1997年） 等の方法が挙げられる。 例えば、 0. 1 mM Bo c -Ph e- S e r— A r g—MCAを基質として 10 OmM Tr i s_HC l pH7. 5、 200 g/ m 1 へパリンの緩衝液中で 20 n g/ m 1 トリプ夕ーゼと室 温で反応させ、 60分後に遊離 MC Aの蛍光カウントを測定する活性測定方法で あり、 好適例として挙げられる。 The method for measuring the activity of tributase is not particularly limited. The method of Schwa rtz et al. (The Journal of Biochemical Chemistry 256, 11939), and the method of Smith et al. (The Journal of Biochemical Chemistry 259 vol. 1) 1046, 1984), Combining et al.'S method (Journal of Medica 1 Chemistry 41, 4854, 1998), Katz et al.'S method (Nature 391, 608, 1998), Cau ghy et al. , The method of The Journal of Immunology, The Journal of Immunology, 6217 (1997), and the method of Waills et al. (P. 264, 676). Is mentioned. For example, 0.1 mM Bo c -Ph e- Ser-Arg-MCA as substrate, 10 OmM Tris_HCl pH 7.5, 200 g / m1 Reaction with 20 ng / m1 trypase in a buffer of heparin at room temperature, 60 minutes This is an activity measurement method for measuring the fluorescence count of free MCA later, and is a preferred example.
上記の系において、 トリプタ一ゼの比活性を  In the above system, the specific activity of tryptase
1 U = 「60分間に Δ蛍光カウントを 1， 000， 000上昇させる トリプ夕ーゼ量」 と定義したとき、 100, 00 OUZmg以上であることが好 ましい。 より好ましくは 140， O O OU/mg以上、 さらに好ましくは 160, 00 OUZmg以上のトリプタ一ゼである。 また、 処理前トリプタ一ゼ の比活性よりも上昇していても構わなく、 好ましい。  1 U = 100,00 OUZmg or more is preferable when defined as "the amount of trypase that increases the Δ fluorescence count by 1,000,000 in 60 minutes". More preferably, the tryptase is 140, OO OU / mg or more, and even more preferably, 160,00 OUZ mg or more. Further, the activity may be higher than the specific activity of the pre-treatment tryptase, which is preferable.
また、 本発明のトリプターゼは、 処理前トリプターゼと比較して、 トリプ ターゼ阻害剤に対する感受性も同様に維持されている。 このためトリプターゼ阻 害剤、 すなわちトリプ夕一ゼのリガンドとの結合様式の検討に用いることが可能 である。  In addition, the tryptase of the present invention maintains the sensitivity to the tryptase inhibitor similarly to the pre-treatment tryptase. Therefore, it can be used for studying the binding mode of a tryptase inhibitor, ie, a tryptic enzyme ligand.
例えば、 処理前トリプターゼに対するトリプターゼ阻害剤に対する I C 50と 比較して、 本発明のトリプ夕一ゼに対する該トリプタ一ゼ阻害剤に対する I C 50が 10〜1000%の範囲内であることが好ましい。 より好ましくは、 30%〜300 %の範囲内である。  For example, the IC 50 for the tryptase inhibitor of the present invention relative to the tryptase inhibitor of the present invention is preferably in the range of 10 to 1000% as compared to the IC 50 for the tryptase inhibitor for tryptase before treatment. More preferably, it is in the range of 30% to 300%.
卜リプターゼ阻害剤とは、 An t i pa i n、 Leupep t i n、 Le e c h— de r i ved トリフタ一" z i nh i b i t o r, d i i s op r op y 1 f l uoropho s pha t e (.The J ou rna l o f B i o l og i c a l Chemi s t ry 259巻 11045頁、 1984年 ) 、 Ben z ami d i n e (B i o l. C h em. Hopp e— S ey l e r 373巻 1025頁 1992年） 、 4—ami d i nophe ney l p y r u v i c a c i d (Na t u r e 392巻 306頁 1998年） 等 に記載されたものが挙げられる。 The tryptase inhibitors are Antipain, Leupeptin, Leech—de ri ved Trifta ”zi nh ibitor, diis op rop y 1 fl uoropho s pha te (.The Jou rna lof Biol og ical Chemi st ry 259 11045, 1984 Hopz e-Seyler 373, 1025, 1992), 4-ami di nopheney lpyruvicacid (Nature 392, 306, 1998), and the like. One.
本発明のトリプ夕一ゼは、 実質的に糖鎖がなく、 実質的に均一であるため通常 の蒸気拡散法 (A.Ducruix and R. Giege:Crystal 1 ization of nucleic Acids and Proteins. A Practical Approach, IRL PRESS at Oxford University Press (1991)p.l30 ) による結晶の作成を、 従来のトリプターゼの結晶の作成よりもか なり迅速に達成できる。 蒸気拡散法では、 多少結晶化する期間の変動はあるが、 一般的な沈殿剤を用いて 2ヶ月以内で結晶を作成できる。 一般的な沈殿剤とは例 えば、 塩化ナトリウム、 硫酸アンモニゥムに代表される無機塩、 種々の分子量の ポリエチレングリコ一ルに代表されるポリオール若しくはそのアルキルエーテル 類、 あるいは、 有機溶媒などである。 好ましい結晶化条件、 例えばポリオールで あるポリエチレングリコ一ルを用いた蒸気拡散法を用いることにより、 結晶を作 成する期間はさらに短縮することができる。 具体的には、 本発明のトリプターゼ は、 30w/"v%ポリエチレングリコール 4000を沈殿剤として用レ これに 更に 0. 2mo 1 /L酢酸アンモニゥムおよび 0. lmo l /L酢酸緩衝液 (pH5. 0) を加えた溶液をリザーバ一溶液とした蒸気拡散法によって 2週間 以内に結晶化できる。 より好ましくは、 1週間以内に結晶化できる。  The trypticase of the present invention is substantially free of sugar chains and is substantially uniform, so that it can be subjected to a conventional vapor diffusion method (A. Ducruix and R. Giege: Crystallization of nucleic Acids and Proteins. A Practical Approach). , IRL PRESS at Oxford University Press (1991) p.l30), which can be achieved much faster than conventional tryptase crystals. In the vapor diffusion method, although the crystallization period varies somewhat, crystals can be formed within two months using a common precipitant. Typical precipitants include, for example, inorganic salts represented by sodium chloride and ammonium sulfate, polyols represented by polyethylene glycol of various molecular weights, alkyl ethers thereof, and organic solvents. By using preferable crystallization conditions, for example, a vapor diffusion method using polyethylene glycol which is a polyol, the period for forming crystals can be further shortened. Specifically, the tryptase of the present invention uses 30 w / "v% polyethylene glycol 4000 as a precipitant, and further contains 0.2 mol / L ammonium acetate and 0.1 mol / L acetate buffer (pH 5.0). ) Can be crystallized within 2 weeks by a vapor diffusion method using a solution containing a reservoir as a reservoir solution, and more preferably within 1 week.
また、 本発明のトリプ夕一ゼは、 トリプ夕ーゼ活性を維持しているため、 トリプターゼ活性を阻害する化合物との複合体結晶の作成も上記と同様の 方法で、 同様の期間で作成することができる。 本発明の第二の態様は、 処理前トリプタ一ゼの酵素活性を維持したまま、 糖鎖 が実質的に切断されたトリプタ一ゼを得る方法である。 具体的には、 天然トリプ ターゼ若しくはリコンビナン卜トリプターゼを、 未変性の状態で糖鎖切断酵素で 処理する工程を含むことを特徴とする、 糖鎖切断処理する前と比較して酵素活性 が 5 0 %以上維持されている、 糖鎖が実質的に切断されたトリプ夕一ゼの製造方 法である。 In addition, since the trypticase of the present invention maintains the trypase activity, complex crystals with a compound that inhibits the tryptase activity can be prepared by the same method as described above for the same period. be able to. A second aspect of the present invention is a method for obtaining a tryptase in which a sugar chain is substantially cleaved while maintaining the enzyme activity of the tryptase before the treatment. Specifically, the method comprises a step of treating a natural tryptase or a recombinant tryptase in a native state with a sugar chain-cleaving enzyme. This method is for producing trypsinase in which the sugar chain is substantially cleaved, which is maintained at not less than 30%.
本発明のトリプターゼを得るための方法は、 トリプターゼを未変性の状態で糖 鎖切断酵素で処理する工程を含むことを特徴とする。  The method for obtaining the tryptase of the present invention is characterized by comprising a step of treating the tryptase in a native state with a sugar chain-cleaving enzyme.
具体的な方法は、 本発明の第一の態様のトリプタ一ゼの項に記載した。  The specific method is described in the section on tryptase of the first aspect of the present invention.
本発明の第三の態様は、 天然トリプターゼ若しくはリコンビナントトリプ夕ー ゼを本発明の第二の態様の方法で前処理して、 結晶化することを特徴とするトリ プタ一ゼ結晶の製造方法である。 具体的には、 天然トリプ夕ーゼ若しくはリコン ピナントトリプターゼを未変性の状態で糖鎖切断酵素で処理する工程を前処理と して含み、 結晶化することを特徴とするトリプタ一ゼ結晶の製造方法である。 また、 天然トリプ夕ーゼ若しくはリコンビナントトリプ夕一ゼを本発明の第二 の態様の方法で前処理した後、 卜リプタ一ゼとァフィ二ティを持つ物質との複合 体を作成し、 結晶化することを特徴とするトリプターゼと、 トリプターゼと ァフィ二ティを持つ物質との複合体結晶の製造方法である。 具体的には、 天 然トリプターゼ若しくはリコンビナントトリプ夕ーゼを未変性の状態で糖鎖切断 酵素で処理する工程で前処理した後、 トリプ夕ーゼとァフィニティを持つ物質と の複合体を作成し、 結晶化することを特徴とするトリプターゼと、 トリプターゼ とァフイエティを持つ物質との複合体結晶の製造方法である。 本発明のトリプターゼ結晶、 若しくは卜リブ夕ーゼと、 トリプターゼと ァフィ二ティを持つ物質との複合体結晶の製造方法は、 天然トリプ夕一ゼ若しく はリコンビナントトリブターゼを未変性の状態で糖鎖切断処理する工程と、 トリプターゼ、 若しくはトリプターゼと、 トリプターゼとァフィニティを持つ物 質との複合体を結晶化する工程を含む。 A third aspect of the present invention is a method for producing a tryptase crystal, comprising pretreating a natural tryptase or a recombinant trypase with the method of the second aspect of the present invention and crystallizing the same. is there. Specifically, the method comprises the step of pretreating native trypsinase or recombinant tryptase with a sugar chain-cleaving enzyme in an undenatured state, and crystallizing the tryptase crystal, characterized in that it is crystallized. It is a manufacturing method. Further, after pre-treating natural trypase or recombinant trypase by the method of the second aspect of the present invention, a complex of the trypticase and a substance having an affinity is prepared and crystallized. And producing a complex crystal of tryptase and a substance having affinity with tryptase. Specifically, after pre-treating natural tryptase or recombinant trypase in a native state with a glycolytic enzyme, a complex of trypase and a substance having affinity is prepared. A method for producing a composite crystal of a tryptase characterized by crystallization, and a substance having tryptase and an affinity. The method for producing a tryptase crystal or a complex crystal of a tryptase and a substance having an affinity with a tryptase according to the present invention comprises the steps of: The method includes a step of performing a chain scission treatment, and a step of crystallizing tryptase or a complex of tryptase and a substance having affinity with tryptase.
糖鎖切断処理する工程は、 本発明の第二の態様の方法の説明の通りである。 本発明の結晶の製造方法は、 本発明の第二の態様の方法を前処理として含むこ とを特徴とし、 前処理したトリプターゼを使用して、 トリプタ一ゼ、 若しく はトリプタ一ゼと、 トリプタ一ゼとァフィニティを持つ物質との複合体を結晶化 する工程はいかなる工程でもよく限定されない。  The step of sugar chain cleavage treatment is as described in the method of the second aspect of the present invention. The method for producing a crystal according to the present invention is characterized in that the method according to the second aspect of the present invention is included as a pretreatment, and using the pretreated tryptase, the tryptase, or the tryptase, The step of crystallizing the complex of the tryptase and the substance having affinity is not limited and may be any step.
蛋白質の結晶化方法は、 静置バッチ法、 自'由界面拡散法、 透析法または蒸気拡 散法 (A. Ducruix and R. Giege:Crystallization of nucleic Acids and Protein s. A Practical Approach, IRL PRESS at Oxford University Press (1991)p.121- 146 ) 等の方法がある。 これらの方法はいずれも沈殿剤によって蛋白質溶液の蛋 白質の溶解度を徐々に下げることで単結晶の析出を行う方法である。 本明細書に 記載の単結晶とは、 前述の結晶化方法を用いた結晶化の過程で引き起こされる蛋 白質の溶解度低下に伴ない析出した一つの結晶核から成長した結晶をいう。 蛋白 質の 3次元構造解析には単結晶が必要であり、 複数の核から成長した結晶から成 る多結晶では解析することができない。  Protein crystallization can be performed using the stationary batch method, free interface diffusion method, dialysis method or vapor diffusion method (A. Ducruix and R. Giege: Crystallization of nucleic Acids and Proteins.A Practical Approach, IRL PRESS at Oxford University Press (1991) p.121-146). In each of these methods, a single crystal is precipitated by gradually lowering the solubility of the protein in the protein solution using a precipitant. The single crystal described in the present specification refers to a crystal grown from one crystal nucleus precipitated due to a decrease in solubility of a protein caused in the course of crystallization using the above-described crystallization method. A single crystal is required for three-dimensional structural analysis of proteins, and cannot be analyzed with a polycrystal consisting of crystals grown from multiple nuclei.
本発明の製造方法における結晶化する工程は、 これらいずれの方法を用いても よく、 またこれらに限定されない。 好ましくは、 蒸気拡散法を用いる工程で ある。 蒸気拡散法には、 沈殿剤を含む大過剰のリザーパー溶液に対する蛋白質を含む ドロップの置き方の違いで、 ハンギングドロップ、 シッティングドロップおよび サンドイッチドロップ蒸気拡散法がある。 これらは、 いずれの方法も、 密閉容器 中にてリザ一バー溶液とド口ップの間の蒸気拡散を利用して、 ド口ップ中の沈殿 剤濃度を上昇させて、 蛋白質の溶解度を下げることで単結晶の析出を促す原理で ある。 より好ましくはシッティングドロップ蒸気拡散法を用いることで良質な単 結晶を得ることができる。 The crystallization step in the production method of the present invention may use any of these methods, and is not limited thereto. Preferably, it is a step using a vapor diffusion method. Vapor diffusion methods include hanging drop, sitting drop, and sandwich drop vapor diffusion, depending on the placement of the protein-containing drop in a large excess of the reservoir solution containing the precipitant. Both methods use the vapor diffusion between the reservoir solution and the reservoir in a closed container to increase the concentration of the precipitant in the reservoir and increase the protein solubility. This is the principle that lowering the concentration promotes the precipitation of single crystals. More preferably, a high-quality single crystal can be obtained by using the sitting drop vapor diffusion method.
この方法は、 密閉容器に入れられた沈殿剤を含む大過剰のリザーバー溶液より 一段高い場所を溶液内に載置された台等で作り、 ここに結晶化する蛋白質の溶液 であるドロップを載置し、 リザ一バ一溶液とドロップ中の平衡化に伴い、 ド口ップ中の沈殿剤濃度が増すため、 ド口ップ中の蛋白質の単結晶が析出するも のである。  In this method, a place one level higher than the large excess reservoir solution containing the precipitant contained in a closed container is created on a table or the like placed in the solution, and a drop, which is a solution of the protein to be crystallized, is placed here. However, as the concentration of the precipitant in the reservoir increases with the equilibration of the reservoir solution and the drop, a single crystal of the protein in the reservoir is deposited.
ドロップは、 トリプターゼ、 低濃度の沈殿剤及び緩衝溶液で調整する。 リザ一 バー溶液は、 高濃度の沈殿剤及び緩衝溶液で調整する。 沈殿剤としては無機塩や ポリオールを用いることができる。 好ましくは無機塩では硫酸アンモニゥム、 ポ リオ一ルではポリエチレンダリコールを用いることができる。 またポリエチレン ダリコールの中でも平均分子量が 1 5 0 0〜8 0 0 0のものを用いるのがより好 ましい。  Drops are prepared with tryptase, low concentrations of precipitants and buffer solutions. The reservoir solution is adjusted with a high concentration of precipitant and buffer solution. Inorganic salts and polyols can be used as precipitants. Preferably, ammonium sulfate can be used for the inorganic salt, and polyethylene dalicol can be used for the polyol. Further, it is more preferable to use polyethylene daricol having an average molecular weight of 150 to 800.
沈殿剤と共にイオン強度を上昇させ蛋白質同士の不要な相互作用を緩衝するた めに、 リザーバー溶液には適当な無機塩を含ませることが好ましい。 好ましい無 機塩としては、 酢酸アンモニゥム、 塩化リチウム、 塩化マグネシウム、 塩化カル シゥム、 塩化カリウム、 塩化アンモニゥム、 酢酸カルシウム、 酢酸カリウム、 酢 酸マグネシウム、 酢酸亜鉛、 酢酸ナトリウムなどが挙げられる。 結晶を析出させ るための； pHは弱酸性〜中性付近の pHが好ましい。 より好ましくは pH4. 5 〜5. 5、 特に好ましくは pH5. 0付近である。 The reservoir solution preferably contains an appropriate inorganic salt in order to increase the ionic strength together with the precipitant and buffer unnecessary interactions between proteins. Preferred inorganic salts include ammonium acetate, lithium chloride, magnesium chloride, calcium chloride, potassium chloride, ammonium chloride, calcium acetate, potassium acetate, and vinegar. Magnesium acid, zinc acetate, sodium acetate and the like. In order to precipitate crystals; the pH is preferably weakly acidic to around neutral. The pH is more preferably from 4.5 to 5.5, and particularly preferably around pH 5.0.
ドロップには、 トリプタ一ゼを 1〜1 Omg/mLに濃縮して含ませることが 好ましい。 より好ましくは 1〜 5mgZmL、 さらに好ましくは 2〜 3 m g /mLに濃縮して含ませる。 さらにドロップにはリザ一バー溶液に、 例えば沈殿 剤、 無機塩等を低濃度で添加することが好ましい。 より好ましくは、 リザーバー 溶液の 1 Z 2の濃度で添加する。 さらにアルキル鎖の両末端にアミノ基を有する 添加剤を用いることが好ましい。 より好ましくはアルキル鎖がペン夕ン程度の長 さの添加剤である。 添加濃度は 0. 1〜2 Owt%が好ましい。 より好ましくは 1 〜10wt%、 さらに好ましくは 3〜7wt%、 特に好ましくは 5wt%である。 結晶化する工程は、 温度を一様にする。 好ましい結晶化温度は 4°C〜30°Cで あり、 より好ましくは 10〜25°C、 さらに好ましくは 20°Cである。  It is preferable that the drop contains tryptase in a concentration of 1 to 1 Omg / mL. More preferably, it is concentrated to 1 to 5 mgZmL, and still more preferably to 2 to 3 mg / mL. Further, it is preferable that a low concentration of, for example, a precipitant, an inorganic salt or the like is added to the reservoir solution for the drop. More preferably, it is added at a concentration of 1 Z 2 of the reservoir solution. Further, it is preferable to use an additive having amino groups at both terminals of the alkyl chain. More preferably, the additive is such that the alkyl chain has a length on the order of pen. The addition concentration is preferably 0.1 to 2 Owt%. It is more preferably 1 to 10% by weight, further preferably 3 to 7% by weight, particularly preferably 5% by weight. The crystallization step makes the temperature uniform. The preferred crystallization temperature is 4 ° C to 30 ° C, more preferably 10 to 25 ° C, and even more preferably 20 ° C.
以上の条件で結晶化する工程を行えば、 通常 4日〜 2ヶ月以内で （幅が 0. 0 7 5 mm以上の大きさの） 結晶化トリプ夕一ゼを製造することがで さる。  By performing the crystallization process under the above conditions, it is usually possible to produce crystallized tryptic (with a width of at least 0.775 mm) within 4 days to 2 months.
また、 本発明の結晶の製造方法は、 トリプタ一ゼのみからなる結晶の製造方法 に限定されず、 トリプターゼと、 トリプタ一ゼとァフィニティを持つ物質との複 合体結晶の製造方法を含む。 複合体結晶の製造方法は、 トリプ夕ーゼと該物質と を結合させる工程を含む。 トリプ夕一ゼとァフィニティを持つ物質とは、 例えば、 卜リプターゼ活性を阻害する化合物が挙げられる。  In addition, the method for producing a crystal of the present invention is not limited to the method for producing a crystal consisting of tryptase alone, but includes a method for producing a complex crystal of tryptase and a substance having affinity with tryptase. The method for producing a composite crystal includes a step of binding trypsinase to the substance. Examples of the substance having affinity with trypsinase include compounds that inhibit tryptase activity.
この工程及び結晶化する工程の順序は特に限定されない。 結合させる工程は前 処理を行う工程と結晶化する工程の間に行ってもよい。 この製造方法による複合 体の結晶化は一般に共結晶化法と言われる。 The order of this step and the step of crystallizing is not particularly limited. Before joining It may be performed between the step of performing the treatment and the step of crystallizing. Crystallization of the composite by this production method is generally called a co-crystallization method.
また、 本発明の製造方法を用いて製造したトリプ夕ーゼ結晶は、 結晶内のトリ プターゼ分子同士の相互作用がトリプ夕一ゼの活性中心近傍とは離れた位置で行 われており、 結晶内に存在する溶媒の流路を通過できる分子量の物質は結晶外部 から結晶を破壊することなく結晶を構成するトリプターゼ分子の活性中心へ到達 可能である。 従って、 トリプターゼとァフィニティを持つ物質が結晶内の溶媒流 路を通過できる場合、 トリプターゼの複合体結晶を製造する場合にソ一キング法 も可能である。  Further, in the trypase crystal produced using the production method of the present invention, the interaction between tryptase molecules in the crystal is performed at a position distant from the vicinity of the active center of trypase, A substance having a molecular weight that can pass through the flow path of the solvent existing in the crystal can reach the active center of the tryptase molecule constituting the crystal from the outside of the crystal without breaking the crystal. Therefore, when a substance having affinity with tryptase can pass through a solvent channel in the crystal, a soaking method is also possible in the case of producing a composite crystal of tryptase.
ソーキング法はすなわち、 前処理したトリプ夕一ゼを結晶化する工程の後、 ト リプタ一ゼと、 トリプターゼとァフィニティを持つ物質とを結合させる工程を行 う方法である。 また、 ソーキング法においては、 既にトリプタ一ゼとァフィ 二ティを持つ物質との複合体として結晶化しているトリプ夕一ゼと、 該ァフィニ ティを持つ物質とは別のァフィ二ティを持つ物質とを結合させる工程でもよい。 既に他の物質との複合体で結晶化しているトリプターゼと該他の物質との結合様 式が非共有結合である場合に有効である。 好ましくは、 トリプターゼのみからな る結晶と該ァフィニティを持つ物質とを結合させる工程である。  The soaking method is a method in which, after the step of crystallizing the pretreated trypase, a step of combining the tryptase with a substance having affinity with tryptase is performed. In the soaking method, a trypticase that has already crystallized as a complex of a tryptase and a substance having an affinity, a substance having an affinity different from the substance having the affinity, May be combined. This is effective when the binding form between tryptase already crystallized in a complex with another substance and the other substance is a non-covalent bond. Preferably, it is a step of bonding a crystal consisting only of tryptase with a substance having the affinity.
共結晶化法の場合、 トリプターゼと、 トリプ夕ーゼとァフィニティを持つ物質 とを結合させる工程は、 前処理したトリプターゼを含む溶液中に該物質を添加す る工程である。 好ましいトリプ夕一ゼの濃度は前記に記載の濃度である。 添加す る該物質の濃度は、 該溶液に含まれるトリプターゼのモル濃度と、 等モル濃度以 上であることが好ましい。 さらに好ましくは 5倍モル濃度以上、 より好ましくは 50倍モル濃度以上である。 In the case of the co-crystallization method, the step of binding tryptase with a substance having affinity with trypase is a step of adding the substance to a solution containing pretreated tryptase. Preferred concentrations of trypsinase are those described above. The concentration of the substance to be added is preferably equal to or higher than the molar concentration of tryptase contained in the solution. More preferably at least 5 times the molar concentration, more preferably More than 50 times molar concentration.
前処理したトリプ夕ーゼを結晶化する工程は、 前記の通りである。  The step of crystallizing the pretreated trypsinase is as described above.
ソーキング法の場合、 前処理したトリプ夕一ゼを結晶化する工程は、 前記の通 りである。  In the case of the soaking method, the step of crystallizing the pretreated trypsinase is as described above.
ソーキング法には結晶が安定に存在しうる溶液が必要であり、 これを人工母液 と呼ぶ。 人工母液は、 上記に記載のリザーバー溶液に 0. 8 5〜 1. 7 mo l/L NaC 1を添加した溶液を用いることができる。 好ましくは 1. 0 mo l/L NaC 1を添加した溶液を用いることである。 この人工母液にトリ プ夕一ゼとァフィニティを持つ物質を、 該物質のトリプターゼに対する Kd値よ りも 10倍以上の濃度で溶解させる。 この溶液をソ一キング溶液として用いる。 好ましくは該物質を Kd値よりも 100倍以上、 より好ましくは 1000倍以上 の濃度で溶解させることである。 複合体結晶化はソ一キング溶液にトリプ夕一ゼ の結晶を浸漬させることで行う。 ソーキングの温度は一様にする。 好ましく は 4°C〜30°Cであり、 より好ましくは 10〜25°C、 さらに好ましくは 20°C である。 以上の条件で行えば、 浸漬時間は通常 12時間〜 4日以内で卜リプ夕ー ゼと該物質との複合体結晶を製造することができる。  The soaking method requires a solution in which crystals can exist stably, and this is called an artificial mother liquor. As the artificial mother liquor, a solution obtained by adding 0.85 to 1.7 mol / L NaCl to the reservoir solution described above can be used. Preferably, a solution to which 1.0 mol / L NaCl is added is used. In this artificial mother liquor, a substance having affinity for trypsinase is dissolved in a concentration 10 times or more higher than the Kd value of the substance for tryptase. This solution is used as a soaking solution. Preferably, the substance is dissolved at a concentration of at least 100 times, more preferably at least 1000 times, the Kd value. Complex crystallization is performed by immersing trypsinase crystals in a soaking solution. The soaking temperature should be uniform. The temperature is preferably 4 ° C to 30 ° C, more preferably 10 to 25 ° C, and still more preferably 20 ° C. Under the above conditions, a complex crystal of tripse and the substance can be produced with the immersion time usually within 12 hours to 4 days.
本発明の製造方法で得られたトリプターゼの結晶若しくはトリプターゼと、 ト リプターゼとァフィニティを持つ物質との複合体結晶は、 結晶の構造解析に用い ることにより、 新規なトリプ夕一ゼ活性を阻害する化合物の創薬に貢献すること ができる。  The crystal of tryptase obtained by the production method of the present invention or a complex crystal of tryptase and a substance having affinity with tryptase inhibits a novel trypase activity by being used for crystal structure analysis. It can contribute to compound drug discovery.
本発明の第四の態様は、 本発明の第一の態様のトリプターゼと、 該トリプ夕ー ゼにァフィニティを有する物質との複^体結晶である。 2003/009738 A fourth aspect of the present invention is a complex crystal of the tryptase of the first aspect of the present invention and a substance having an affinity for the trypase. 2003/009738
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該トリプ夕ーゼにァフィ二ティを有する物質は、 トリプターゼ活性を阻害する 化合物であることが好ましい。  The substance having an affinity for trypsinase is preferably a compound that inhibits tryptase activity.
本発明の第一の態様の卜リプターゼは、 本発明の第一の態様で説明された通り である。  The tryptase of the first aspect of the present invention is as described in the first aspect of the present invention.
本発明の複合体結晶の製造方法は、 本発明の第三の態様で説明された通りであ る。  The method for producing the composite crystal of the present invention is as described in the third embodiment of the present invention.
本発明の第五の態様は、 トリプターゼと特定の新規なトリプターゼ活性を阻害 する化合物との複合体結晶である。 具体的には、 トリプターゼと N— [2- [N 一 [3— [4— (アミノメチル） フエニル] プロピル] ァミノ] ェチル] —2— ナフタレンスルホンアミド若しくはその塩との複合体結晶である。 また、 トリプ ターゼと N— [2— [N- [3— [4- (アミノメチル) フエニル] プロピル] 一 N—メチルァミノ] ェチル] —2—べンゾ [b] チォフェンカルボキサミド若 しくはその塩との複合体結晶である。  A fifth aspect of the present invention is a complex crystal of tryptase and a compound that inhibits a specific novel tryptase activity. Specifically, it is a composite crystal of tryptase and N- [2- [N- [3- [4- (aminomethyl) phenyl] propyl] amino] ethyl] -2-naphthalenesulfonamide or a salt thereof. Tryptase and N- [2- [N- [3- [4- (aminomethyl) phenyl] propyl] -N-methylamino] ethyl] -2-benzo [b] thiophenecarboxamide or This is a composite crystal with a salt.
塩とは、 特に限定されない。 製造時において、 トリプ夕ーゼとの複合体を考慮 すると比較的分子量が小さい塩が好ましい。 例えば無機塩である。 より好ましく は、 ホウ酸塩、 硫酸塩または塩酸塩である。 特に好ましくは塩酸塩である。 複合体結晶の製造方法は本発明の第三の態様の説明の通りである。 トリプター ゼと N— [2- [N— [3— [4— (アミノメチル） フエニル] プロピル] アミ ノ] ェチル] —2—ナフタレンスルホンアミド （化合物 Aと記載することがある ) 及び N— [2- [N- [3— [4一 （アミノメチル） フエニル] プロピル] 一 N—メチルァミノ] ェチル] —2—べンゾ [b] チォフェン力ルポキサミドニ塩 酸塩 （化合物 Bと記載することがある） の製造方法は、 その一例を後述する実施 例 8に記載した。 The salt is not particularly limited. At the time of production, a salt having a relatively small molecular weight is preferable in consideration of a complex with trypsinase. For example, an inorganic salt. More preferably, it is a borate, a sulfate or a hydrochloride. Particularly preferred is the hydrochloride. The method for producing the composite crystal is as described in the third embodiment of the present invention. Tryptase and N— [2- [N— [3 -— [4- (aminomethyl) phenyl] propyl] amino] ethyl] —2-naphthalenesulfonamide (sometimes described as compound A) and N— [ 2- [N- [3- [4- (Aminomethyl) phenyl] propyl] -1-N-methylamino] ethyl] —2-benzo [b] thiophene lipoxamidini hydrochloride (may be described as compound B The production method of Described in Example 8.
上記の複合体結晶から、 後述する本発明の第六の態様に記載の構造解析を行う ことにより、 複合体の立体構造座標を得ることができる。 得た構造解析座標を解 析することによって、 ヒト /3トリプ夕一ゼを選択的に阻害する化合物 Aまたは化 合物 Bとヒト 3トリプターゼが相互作用するアミノ酸残基を特定することが可能 である。 また、 既存の分子設計ソフトウェア (トライボス社 SYBYL,アクセルリス 社 Ins ight l l等） によって複合体分子の座標を表示させ相互作用に関わるァミノ 酸残基を抽出することで、 特に産業での応用に重要な性質や情報を抽出すること も可能である。 たとえば、 複合体の結晶構造において、 化合物 Aまたは化合物 B と、 数オングストローム以内の距離に存在するヒト ]3トリプターゼのアミノ酸残 基を抽出すれば、 直接的な相互作用を有しているヒト /3トリプ夕ーゼ上のアミノ 酸残基が抽出若しくは特定可能である。 このように得られた立体構造座標を用い ることにより、 ヒト ]3トリプターゼを選択的に阻害する化合物のフアルマコフォ ァ抽出をすることができる。 また、 ヒト i3トリプ夕ーゼを選択的に阻害する化合 物をコンピュータを用いてスクリーニングを行うことができる。 またヒト /3トリ プターゼを選択的に阻害する化合物の分子設計 （活性上昇、 選択性付与など） 等 を行うことができる。 これらの詳細な説明は後述する本発明の第六の態様、 第七 の態様に記載されている。  The three-dimensional structure coordinates of the complex can be obtained from the above-described complex crystal by performing the structural analysis described in a sixth aspect of the present invention described below. By analyzing the obtained structural analysis coordinates, it is possible to identify the amino acid residues at which compound A or compound B, which selectively inhibits human / 3 trypase, interacts with human 3 tryptase. is there. In addition, by displaying the coordinates of the complex molecules and extracting the amino acid residues involved in the interaction by using existing molecular design software (SYBYL, Tribos, Insellll, Accelrys, etc.), it is particularly important for industrial applications. It is also possible to extract various properties and information. For example, in the crystal structure of the complex, extraction of the amino acid residue of compound A or compound B with the amino acid of human] 3 tryptase within a distance of several angstroms, Amino acid residues on trypsinase can be extracted or identified. The pharmacophore extraction of a compound that selectively inhibits human] 3 tryptase can be performed by using the thus obtained three-dimensional structure coordinates. In addition, a compound that selectively inhibits human i3 trypsinase can be screened using a computer. In addition, molecular design of compounds that selectively inhibit human / 3 tryptase (increase in activity, selectivity, etc.) can be performed. These detailed descriptions are described in the sixth and seventh embodiments of the present invention described later.
本発明の第六の態様は、 新規なトリプターゼ活性を阻害する化合物のスクリ一 ユング方法で、 二種類に分けられる。 第一は、 以下の工程を含むことを特徴とす るトリプ夕ーゼ活性を阻害する化合物のスクリーニング方法である。  The sixth embodiment of the present invention is a novel method for screening compounds that inhibits tryptase activity, and is classified into two types. The first is a method for screening for a compound that inhibits trypsinase activity, comprising the following steps.
①糖鎖切断したトリプタ一ゼとあらかじめトリプ夕一ゼ活性を阻害すること がわかっている化合物との複合体結晶を作成する工程 (1) Inhibition of the sugar chain-cleaved tryptase and trypticase activity in advance Of forming a composite crystal with a compound whose composition is known
②前記作成した結晶の構造を解析し、 糖鎖が切断されたトリプ夕一ゼと前記 化合物との相互作用から、 トリプターゼ活性を阻害する化合物のフアルマコフォ ァを作成し、 トリプターゼ活性を阻害する化合物をバーチャルで選択する工程 ③バーチャルで選択した前記化合物をリアルで用意する工程、 及び (2) Analyze the structure of the crystal prepared above, and create a pharmacophore of a compound that inhibits tryptase activity based on the interaction between the sugar chain-cleaved trypticase and the compound, and identify the compound that inhibits tryptase activity. A step of preparing virtually the compound ③ a step of preparing the compound selected in a virtual manner, and
④用意した前記化合物の卜リプ夕ーゼ活性に対する影響を測定する工程。 本スクリーニング方法を用いることにより、 ランダムに化合物を用いて、 トリ プ夕ーゼ活性に対する影響をスクリ一ニングするよりも、 ヒット化合物の確率が 高くなる。 (4) a step of measuring the effect of the prepared compound on trypticase activity. By using this screening method, the probability of a hit compound is higher than using a compound at random and screening for the effect on trypase activity.
①の工程は、 本発明の第 3の態様の結晶の製造方法を用いて、 糖鎖切断したト リプターゼとあらかじめトリプターゼ活性を阻害することがわかっている化合物 との複合体結晶を作成する工程である。 例えば、 W099/40073号公報に 記載の化合物、 APPAを用いてもよい。 また、 公知とはなっていないが実施者 がトリプ夕一ゼ活性を阻害する化合物であるという知見を得ている化合物を用い てもよい。  The step (1) is a step of using the method for producing a crystal according to the third embodiment of the present invention to form a complex crystal of a glycosylated treptase and a compound which is known to inhibit tryptase activity in advance. is there. For example, the compound described in WO99 / 40073, APPA, may be used. Further, a compound that is not known but has been obtained by the practitioner that the compound inhibits trypsinase activity may be used.
②の工程は、 ①の工程で作成した結晶の構造を解析し、 糖鎖切断した トリプ夕一ゼと前記化合物との相互作用から、 トリプターゼ活性を阻害する化合 物のフアルマコフォアを作成し、 トリプタ一ゼ活性を阻害する化合物を バ一チャルで選択する工程である。  In the step (2), the structure of the crystal prepared in the step (1) is analyzed, and a pharmacophore of a compound that inhibits the tryptase activity is prepared from the interaction between the sugar chain-cleaved trypsinase and the compound. This is a step of selecting a compound that inhibits the activity in a virtual manner.
複合体結晶の構造解析は実験室の X線回折計または大型放射光施設 （ES RF、 APS, SP r i ng— 8、 PF、 ALS、 CHESS、 SRS、 LLN L、 SSRL、 B r o o k h a v e nなど） を用いて、 振動写真法やラウエ法に よってイメージングプレートまたは C C Dカメラなどの 2次元検出器を用い てデータの収集を行い、 該データよりトリプターゼと前記活性調節剤の複合体の 3次元構造を X線結晶構造解析により明らかにすることができる。 具体的には、 X線回折実験により収集された回折イメージをデータ処理ソフトウェアで処理す ることで、 個々の回折斑点の指数と積分によって得られた回折強度を算出で きる。 回折斑点は本トリプ夕一ゼ結晶の場合約 1 0万以上にものぼる。 これらの 回折斑点の指数と積分強度を用いて逆フーリェ変換を行うことで 3次元空間の電 子密度を導くのであるが、 回折実験では電子密度の計算に必要な各回折斑点の位 相の情報を測定することは原理的に不可能である。 そこで電子密度を得るために は、 分子置換法、 重原子同型置換法、 多波長異常分散法またはそれらの改変法に よって失われた情報である位相を推定しなければならない。 トリプ夕一ゼの場合 は分子置換法を用いるのが好ましい。 Structural analysis of the complex crystal is performed using a laboratory X-ray diffractometer or a large synchrotron radiation facility (ES RF, APS, SP rigning-8, PF, ALS, CHESS, SRS, LLNL, SSRL, Brookhaven, etc.) For vibration photography and Laue Therefore, data can be collected using a two-dimensional detector such as an imaging plate or a CCD camera, and the three-dimensional structure of the complex of tryptase and the activity modulator can be determined from the data by X-ray crystal structure analysis. . Specifically, by processing the diffraction images collected by X-ray diffraction experiments with data processing software, the diffraction intensity obtained by integrating the index of each diffraction spot and the integration can be calculated. Diffraction spots amount to about 100,000 or more in the case of this tryptic crystal. The inverse Fourier transform is performed using the index of the diffraction spots and the integrated intensity to derive the electron density in a three-dimensional space.In the diffraction experiment, information on the phase of each diffraction spot required for calculating the electron density is obtained. It is impossible in principle to measure. Therefore, in order to obtain the electron density, it is necessary to estimate the phase, which is the information lost by the molecular replacement method, the heavy atom isomorphous replacement method, the multi-wavelength anomalous dispersion method, or a modification thereof. In the case of trypsinase, it is preferable to use a molecular replacement method.
分子置換法は解析対象の蛋白質と 3次元構造の相同性が高い蛋白質の 3次元座 標を探索モデルとして結晶内の格子に解析対象分子がどのように配向し、 結晶を 構成しているかを推定する方法である。 探索モデルを使った擬似的な結晶の構成 を推定できれば、 そこからフーリエ変換を行うことで各回折斑点の位相情報を推 定できる。 この推定した位相情報を、 測定された回折斑点強度と合わせて 逆フ一リェ変換を行う。 これらはすべて計算機上でソフトウェアによって行われ るため、 実験が不要であり且つ非常に迅速に解析を行うことができる。 このよう にして得られた電子密度図に合わせて、 3次元モデルをグラフィックスワークス テーション上で稼動するソフトウェアを用いて構築する。 このモデル構築の後、 最小二乗法、 最尤法、 S i m u l a t e d A n n e a l i n g法などによる構 造の精密化を行うことで最終的な複合体の 3次元構造を得る。 The molecular replacement method uses the 3D coordinates of the protein with a high degree of homology to the protein to be analyzed as a search model to estimate how the molecule to be analyzed is oriented in the lattice within the crystal and constitutes the crystal How to If we can estimate the structure of the pseudo crystal using the search model, we can estimate the phase information of each diffraction spot by performing a Fourier transform from it. The estimated phase information is subjected to inverse Fourier transform together with the measured diffraction spot intensity. These are all performed by software on a computer, so no experiments are required and the analysis can be performed very quickly. According to the electron density map obtained in this way, a 3D model is constructed using software running on a graphics workstation. After constructing this model, it is constructed using the least squares method, maximum likelihood method, Simulated Annealing method, etc. The structure is refined to obtain the final three-dimensional structure of the complex.
トリプターゼと前記トリプ夕ーゼ活性を阻害する化合物の複合体の 3次元構造 より、 トリプターゼと前記化合物とのフアルマコフォアを作成することが できる。  From the three-dimensional structure of the complex of tryptase and the compound that inhibits trypsinase activity, a pharmacophore of tryptase and the compound can be prepared.
フアルマコフォアとは、 標的蛋白質に結合するために必要とされる、 化合物上 の物理化学的特徴である。 フアルマコフォアは、 化合物の特定の官能基間の相対 距離を決定することで定義することも可能であり、 また構造上の物理化学的特徴 を特性球として表し、 特性球間の相対距離を決定することで定義することも可能 である。 また、 構造上の物理化学的特徴の一つを、 蛋白質との相互作用、 蛋白質 との距離で、 フアルマコフォアの一つのサイトとして定義し、 サイトの集合とし てフアルマコフォアを定義することも可能である。 その他、 当業者が通常用い得 る手法を任意に使用してフアルマコフォアを定義可能であり、 前述の方法に限定 されるものではない。  A pharmacophore is a physicochemical feature on a compound that is required to bind to a target protein. A pharmacophore can be defined by determining the relative distance between specific functional groups of a compound, and by expressing structural physicochemical characteristics as characteristic spheres and determining the relative distance between characteristic spheres. It is also possible to define It is also possible to define one of the structural physicochemical characteristics as one site of the pharmacophore based on the interaction with the protein and the distance from the protein, and define the pharmacophore as a set of sites. In addition, the pharmacophore can be defined by any method commonly used by those skilled in the art, and is not limited to the method described above.
特性球とは、 疎水性、 帯電性、 水素結合を形成し得る能力、 などの種々の物理 化学的性質を保持した空間的領域を意味する。 例えば、 フアルマコフォア 構築プログラムである Catalyst (Accel rys Inc., San Diego, CA) においては、 「Hydrogen - bond Acceptor (さらに、 Hydrogen-bond Acceptor lipidを分類する こともできる） 」 、 「Hydrogen-bond Donor 」 、 「Hydrophobic (さらに、 Hydrophobic Aromaticと Hydrophobic aliphatic を分類 ることもできる) 」 、 「Negative Charge 」 、 「Negative Ionizablej 、 「Positive Charge 」 、 rpositive Ionizablej 、 厂 Ring A謹 tic 」 の 8種類の特性球が示されている が、 該プログラムのユーザーが新たな定義を加えることも可能であり、 上記の構 成要素以外を利用することも可能である。 すなわち、 疎水性領域、 水素結合受容 体領域、 陽イオン領域、 環状芳香族性領域、 等を物理化学的性質として規定し、 これら該物理化学的性質を有する球状の領域として、 特性球を表すことがで きる。 各特性球に適合する原子や官能基の例は、 例えば Catalys tなどのプロダラ ムに付属のマニュアルに定義されている （Accel rys Inc. , Catalys t Document at i on Re l ease 4. 5， 1999 ) 。 The characteristic sphere refers to a spatial region that retains various physicochemical properties such as hydrophobicity, chargeability, ability to form hydrogen bonds, and the like. For example, in the pharmacophore construction program Catalyst (Accelrys Inc., San Diego, CA), "Hydrogen-bond Acceptor (furthermore, Hydrogen-bond Acceptor lipid can be classified)", "Hydrogen-bond Donor" , "Hydrophobic" (also classified as Hydrophobic Aromatic and Hydrophobic aliphatic), "Negative Charge", "Negative Ionizablej", "Positive Charge", rpositive Ionizablej, and "Factory Ring A". Although it is shown, it is possible for the user of the program to add a new definition. It is also possible to use components other than components. That is, the hydrophobic region, the hydrogen bond acceptor region, the cation region, the cyclic aromatic region, etc. are defined as physicochemical properties, and the characteristic sphere is represented as a spherical region having these physicochemical properties. I can do it. Examples of atoms and functional groups suitable for each characteristic sphere are defined in the manual attached to the program such as Catalyst (Accelrys Inc., Catalyst Document at ion Relax 4.5, 1999). ).
すなわち、 本発明のスクリーニング方法の①の工程で得られるフアルマコフォ ァは、 上記の特性球として表すと、 トリプターゼと、 トリプタ一ゼとの複合体結 晶に用いた化合物の蛋白質一リガンド相互作用部位に適合した特性球または特性 球の集合で表される。  That is, the pharmacophore obtained in step (1) of the screening method of the present invention, when expressed as the above-mentioned characteristic sphere, is located at the protein-ligand interaction site of the compound used for the complex crystallization of tryptase and tryptase. It is represented by a matching characteristic sphere or set of characteristic spheres.
さらに前記で作成したフアルマコフォアから、 トリプ夕ーゼ活性を阻害する化 合物をバーチャルで選択する工程は、 前記で作成したフアルマコフォアから、 ト リプタ一ゼ活性を阻害する化合物をバーチヤルで選択する工程であれば限定され ない。  Further, the step of virtually selecting a compound that inhibits trypsinase activity from the pharmacophore prepared as described above includes a step of vertically selecting a compound that inhibits the activity of tryptase from the pharmacophore prepared above. If there is, it is not limited.
「バーチャルで選択する」 とは、 実際に想定しうる化合物を想定し、 候補化合 物の阻害作用を試験せずに、 紙面上若しくはコンピューター上でトリプターゼ活 性を阻害する化合物を選択することを言う。  `` Virtual selection '' refers to the selection of compounds that inhibit tryptase activity on paper or on a computer without testing the inhibitory effect of the candidate compound, assuming a compound that can be actually assumed. .
例えば、 紙面上でフアルマコフォアの各条件に該当する官能基を記載し、 官能 基の性質を阻害しないリンカーを用いて各官能基を繋ぐ設計をすることにより、 化合物を選択する工程が挙げられる。  For example, there is a step of selecting a compound by describing a functional group corresponding to each condition of the pharmacophore on a paper surface and designing each functional group by using a linker that does not inhibit the properties of the functional group.
好ましくは、 前記フアルマコフォアをコンピューターソフトウェアに供用する ことにより、 トリプタ一ゼ活性を阻害する化合物をバーチャルで選択する工程で ある。 より好ましくは任意の適切なコンピュータ一ソフトウェアで、 分析、 解析、 またはソフトウェアを利用することにより、 新規なトリプターゼ活性を阻 害する化合物をバーチャルで選択する工程である。 また、 任意の適切な コンピュータ一ソフトウエアで、 前記フアルマコフォアの各条件に該当するよう に分子を設計する工程でもよい。 Preferably, in the step of virtually selecting a compound that inhibits tryptase activity by applying the pharmacophore to computer software, is there. More preferably, it is a step of virtually selecting a compound that inhibits novel tryptase activity by analysis, analysis, or using software with any appropriate computer software. Further, the molecule may be designed using any appropriate computer software so as to meet the respective conditions of the pharmacophore.
図 2に上記したスクリ一ニング方法の概要を示す。  Fig. 2 shows the outline of the above-mentioned screening method.
用いるコンピュータ一ソフトウェアは、 リガンドからの化学的機能の抽出およ び抽出した化学的機能と類似した空間配置を取り得る化合物の検索が可能な ソフトウェアであれば何を用いても良く、 例えば Catalys t (アクセルリス社） 、 Sybyl (トライポス社） のモジュールである Uni ty 等が挙げられる。 この際、 ィ匕 合物の構造 ·物性等の類似度により化合物を分類する必要があれば、 Dayl ight ( Dayl ight Chemi cal Informat ion Sys tems, Inc. , Mi ss i on Vi e j o, CA) 等のフロ グラムを使用することが可能である。  The computer software used may be any software that can extract a chemical function from a ligand and search for a compound that can take a spatial configuration similar to the extracted chemical function. (Accelris) and Sybyl (Tripos). At this time, if it is necessary to classify the compound according to the similarity of the structure and physical properties of the compound, Daylight (Daylight Chemical Information Systems, Inc., Missions on Viejo, CA), etc. It is possible to use the following program.
以下に、 解析用ソフトウェアとして Catalys t (アクセルリス社） を使用した例 を示す。 フアルマコフォアを用いて、 あらかじめ準備したコンピュータスクリー ニング用の化合物構造デ一夕ベースを対象としてスクリーニングを実施す る。 フアルマコフォアの情報とある化合物の立体構造の空間配置とを比較し、 該 化合物がそのフアルマコフォアの性質を満足させるものであるかどうかを計算に より決定する。 例えば、 化合物の立体構造を構造座標化する段階、 該構造座標と フアルマコフォアを規定する特性球の構造座標とを対比させる段階、 化合物の立 体構造の構造座標がフアルマコフオアにおける少なくとも 3点以上の特性球の相 対配置を満足させることを確認する段階を含み得る。 コンピュータスクリーニング用の化合物構造データベースは以下のようにして 構築する。 1 ) 化合物の三次元化： CONCORD (トライボス社） あるいは C0RINA ( Mo l ecul ar Networks GmbH Computerchemi e社） などの三次元構造発生プログラム を用いて、 標準的な結合角、 適切な結合長を有する初期配座を発生させる。 2 ) 立体配座の発生：システマチックサ一チなどのアルゴリズムを用いて （回転 可能な結合を適当な回転角で回転させて新しい配座を得る手法) 初期配座から化 合物が取りうる配座を多数生成させる。 得られた配座より生成エネルギーが最も 小さぃ最安定配座を見出し、 適当な生成エネルギーの配座のみを検索対象とする (例えば最安定配座から生成エネルギーが 2 O kcal/mo l以下） 。 An example using Catalyst (Accelris) as the analysis software is shown below. Using a pharmacophore, screening is performed on a compound structure database prepared for computer screening prepared in advance. The information on the pharmacophore is compared with the spatial arrangement of the steric structure of a compound, and it is determined by calculation whether or not the compound satisfies the properties of the pharmacophore. For example, the step of converting the three-dimensional structure of the compound into structural coordinates, the step of comparing the structural coordinates with the structural coordinates of the characteristic sphere defining the pharmacophore, the step of comparing the structural coordinates of the stereostructure of the compound with at least three points in the pharmacophore May be included to confirm that the relative arrangement of the two is satisfied. A compound structure database for computer screening is constructed as follows. 1) Three-dimensionalization of the compound: Using a three-dimensional structure generation program such as CONCORD (Tribos) or C0RINA (Molecular Networks GmbH Computerchemie), an initial compound with a standard bond angle and appropriate bond length is used. Generate conformation. 2) Generation of a conformation: a method for obtaining a new conformation by rotating a rotatable bond at an appropriate rotation angle using an algorithm such as a systematic search. Generate many conformations. From the obtained conformation, the generated energy is the smallest. The most stable conformation is found, and only the conformation with the appropriate generated energy is searched. (For example, the generated energy from the most stable conformation is 2 O kcal / mol or less.) .
コンピュータ一ソフトウェアに供用することにより、 蛋白質を阻害する化合物 をバーチャルで選択する工程、 すなわちコンピュータスクリ一二ングの利点とし て、 検索対象が理論上考え得る全ての化合物の部分集合であることが挙げら れる。 通常は、 自社で保有する化合物のデータベース、 市販化合物データ ベース、 例えば Avai l ab l e Chemi cal s Di rec tory (MDL 社） や各化合物販売会社 ·代理店が作成したデータベース、 もしくはバーチャルコンビナトリアル合成手 法等を用いて発生させた仮想化合物のデー夕ベース、 天然物由来の化合物デー夕 ベース、 医薬品データベース等をコンピュータ検索用に変換して用いる。  A process of virtually selecting a compound that inhibits a protein by applying it to computer software, that is, the advantage of computer screening is that the search target is a subset of all theoretically conceivable compounds. Is received. Usually, a database of compounds owned by the company, a commercially available compound database, for example, Avali- ble Chemicals Directory (MDL) or a database created by each compound sales company or agency, or a virtual combinatorial synthesis method. The database of virtual compounds generated using the above, the database of compounds derived from natural products, the database of pharmaceuticals, etc. are converted and used for computer search.
このようにして、 上記コンピュータスクリーニングによりヒットした化合 物は、 トリプターゼに結合する可能性を有する化合物であるため、 トリプ夕ーゼ 活性を阻害する化合物となり得る可能性が、 一定の確率で発生する。  In this way, since the compound hit by the above-described computer screening is a compound that has a possibility of binding to tryptase, there is a certain probability that the compound may be a compound that inhibits trypsase activity.
また、 フアルマコフォアをコンピューターソフトウエアに供用することに より、 前記フアルマコフォアを満たすトリプ夕一ゼ活性を阻害する化合物 38 In addition, a compound that inhibits trypsinase activity that satisfies the pharmacophore by applying the pharmacophore to computer software 38
3 5  3 5
をバーチャルで選択する工程は、 後述する本発明のドラッグデザィン方法により ドラッグデザィンする工程も含まれ、 好ましく例示される。 The step of virtually selecting is preferably exemplified, including the step of drag designing according to the drag designing method of the present invention described later.
以上に説明したコンピューターを利用した工程は、 トリプ夕ーゼ活性を阻害す る化合物の迅速なスクリーニングを可能とするが、 ヒットした化合物群は、 期待 される活性を有する確率が高くはなるが、 全ての化合物が活性を有するとは限ら ないため、 望ましくは次の段階として実際に化合物を合成、 変性、 取得、 購入し たりして用意して、 その用意した化合物を実験的に評価することが必要となる。 したがって、 コンピュータースクリーニングの結果から実験的に評価する化合 物を選択する際には、 評価の結果期待される活性化合物数を考慮の上、 実際に実 験的に評価を行う化合物数を決定する必要がある。  The computer-based process described above allows for rapid screening of compounds that inhibit trypsinase activity, but the hit compound group has a high probability of having the expected activity. Since not all compounds have activity, it is desirable to actually prepare, synthesize, modify, acquire, or purchase compounds as the next step, and evaluate the prepared compounds experimentally. Required. Therefore, when selecting compounds to be evaluated experimentally from the results of computer screening, it is necessary to determine the number of compounds to be evaluated experimentally, taking into account the expected number of active compounds as a result of the evaluation. There is.
一般的に、 コンピュータ一スクリーニングを行うプログラムには評価システム が含まれるが、 評価システムは、 対応するプログラムのアルゴリズムに合わせた 独自の手法が多い。 評価システムとして各化合物の活性値が得られる場合は、 そ の値を基準として実験的評価に供する化合物を選択することが可能であるが、 活 性値ではなく経験的な数値しか得られない評価システムも数多く存在する。 一方 で、 コンピュータ一スクリーニングの目的が、 実験的評価に供する化合物数を絞 り込むことと考えると、 評価システムにより順位付けられた化合物を、 上位から 実験に供することが可能な数だけ選択してもよい。 例えばコンピュータース クリーニングにより選択された化合物が期待する活性を有する確率を 5 % ~ 3 0 %と考えた場合、 活性制御物質を 1 0化合物得るためには約 3 0〜 2 0 0化 合物を選択すれば良いし、 活性制御物質を 5 0化合物得るためには約 1 6 0 〜1 0 0 0化合物を選択すれば良い。 この際、 最終的に得られる活性制御化合物 に多様性を持たせることを目的として、 評価の上位化合物を構造 ·物性等の類似 度により分類した後、 各分類した群から実験的評価に供する化合物数を選択して もよい。 Generally, a computer-screening program includes an evaluation system, but many evaluation systems have their own unique methods that match the algorithm of the corresponding program. If the activity value of each compound can be obtained as an evaluation system, it is possible to select a compound to be subjected to experimental evaluation based on that value, but an evaluation that can obtain only empirical numerical values instead of activity values There are many systems. On the other hand, assuming that the purpose of computer-based screening is to narrow down the number of compounds to be subjected to experimental evaluation, the number of compounds ranked by the evaluation system is selected by the number that can be used for experiments from the top. Is also good. For example, assuming that the probability that the compound selected by computer screening has the expected activity is 5% to 30%, about 30 to 200 compounds are required to obtain 10 compounds as an activity controlling substance. What is necessary is just to select, and in order to obtain 50 compounds as an activity controlling substance, about 160 to 1000 compounds may be selected. At this time, the activity control compound finally obtained For the purpose of imparting diversity to the data, it is also possible to classify the top compounds in the evaluation based on similarities such as structural and physical properties, and then select the number of compounds to be subjected to experimental evaluation from each classified group.
③の工程は、 前記選択した化合物を用意する工程である。 すなわち②の工程で 紙面上、 コンピュータ一上等でバーチャルで選択された化合物を、 実際に用意す る工程である。 ②の候補化合物のトリブターゼ阻害という用途が新規であつ ても、 既知の化合物であれば、 市販品を購入してもよく、 また既知の方法を利用 して合成すればよい。 新規な化合物の場合には、 その化合物の官能基等の構造に 応じて適宜合成すればよレ ^。  Step (3) is a step of preparing the selected compound. In other words, this is the process of actually preparing the compound that was virtually selected on paper or on a computer in step (2). Even if the use of the candidate compound (2) for inhibiting trybutase is novel, a commercially available product may be purchased as long as it is a known compound, or it may be synthesized using a known method. In the case of a novel compound, it may be appropriately synthesized according to the structure of the compound such as a functional group.
④の工程は、 ③で合成した候補化合物のトリプターゼ活性に対する影響を in vi troの系および/または in vivo の系にて測定する工程である。 トリプタ一 ゼ活性に対する影響の測定が可能であれば、 in vi t ro試験であってもよ いし、 in vivo試験であってもよい。 in vi tro試験はより簡便に行うことができ る。 in vivo試験はより生体内を反映するので将来医薬品とすることができる可 能性が上昇する。  Step (2) is a step of measuring the effect of the candidate compound synthesized in (3) on tryptase activity in an in vitro system and / or an in vivo system. As long as the effect on tryptase activity can be measured, an in vitro test or an in vivo test may be used. In vitro tests can be performed more easily. In vivo tests reflect more in vivo, increasing the potential for future drug use.
例えば、 in vi tro試験を本発明の第一の態様に記載した活性測定方法を用いて 行えばよい。 ただし、 ④の工程は、 これらに限定されない。  For example, an in vitro test may be performed using the activity measurement method described in the first embodiment of the present invention. However, the step (2) is not limited to these.
第二のスクリーニング方法は、 ①後述する実施例 6に記載の表 1の条件 1〜4 をすベて満たすフアルマコフォアをコンピュータ一ソフトウェアに供用すること により、 当該フアルマコフォアを満たすヒト /3トリプタ一ゼ活性を阻害する化合 物をバーチャルで選択する工程を含むことを特徴とするトリプターゼ活性を阻害 する化合物のスクリ一ニング方法である。 また、 ①後述する実施例 6に記載の表 2の条件 1〜 4をすベて満たすフアルマ コフォアをコンピューターソフトウエアに供用することにより、 当該フアルマコ フォアを満たすヒト /3トリプ夕ーゼ活性を阻害する化合物をバーチャルで選択す る工程を含むことを特徴とするヒト βトリプ夕一ゼ活性を阻害する化合物のスク リーニング方法である。 The second screening method is as follows: (1) A pharmacophore that satisfies all of the conditions 1 to 4 in Table 1 described in Example 6 described below is applied to a computer software so that a human / 3 tryptase activity that satisfies the pharmacophore is obtained. A method for screening a compound that inhibits tryptase activity, which comprises a step of virtually selecting a compound that inhibits tryptase activity. In addition, (1) the human / 3 trypsinase activity that satisfies the pharmacophore is inhibited by applying the pharmacophore satisfying all of the conditions 1 to 4 in Table 2 described in Example 6 to computer software. A method for screening a compound that inhibits human β-trypticase activity, comprising a step of virtually selecting a compound to be tested.
表 1または表 2に記載のフアルマコフォアは、 本発明の第四の態様の複合体結 晶を解析し後述する実施例 7に記載の方法より得られる。  The pharmacophore described in Table 1 or Table 2 is obtained by analyzing the complex crystal of the fourth embodiment of the present invention and obtaining the same by the method described in Example 7 described later.
表 1に記載のフアルマコフォアについて説明する。  The pharmacophore described in Table 1 will be described.
表 1に記載のフアルマコフォアの条件 1及び条件 2は、 ヒト iSトリプターゼの S 1ポケットとの相互作用を規定する条件であり、 ヒト i3トリプタ一ゼ活性を阻 害する上で、 重要なフアルマコフォアの条件である。  The pharmacophore conditions 1 and 2 described in Table 1 are conditions that regulate the interaction of the human iS tryptase with the S1 pocket, and are important pharmacophore conditions in inhibiting human i3 tryptase activity. is there.
表 1に記載のフアルマコフオアの条件 2の疎水性官能基は、 好ましくは芳香環 もしくは環状炭化水素である。 また、 疎水性官能基の重心がトリプターゼと立体 障害をおこさずに存在することである。  The hydrophobic functional group of Condition 2 of the pharmacophore described in Table 1 is preferably an aromatic ring or a cyclic hydrocarbon. Also, the center of gravity of the hydrophobic functional group is present without causing steric hindrance to tryptase.
表 1に記載のフアルマコフォアの条件 3は、 ヒト /3トリプ夕一ゼに特異的 な 9 0番ループとの相互作用を規定する条件で有る。  The pharmacophore condition 3 described in Table 1 is a condition that regulates the interaction with the 90th loop specific to human / 3 trypase.
また、 ヒト 3トリプターゼは 4量体を形成するため、 表 1に記載のフアルマコ フオアの条件 4は、 隣接するトリプターゼとの相互作用をも規定する条件で ある。 隣接するトリプターゼとは、 後述する図 4に記載の A— Dの関係 （B _ C の関係も等価） にあたるトリプターゼである。  Further, since human 3 tryptase forms a tetramer, condition 4 of the pharmacophore described in Table 1 is a condition that also defines an interaction with an adjacent tryptase. The adjacent tryptase is a tryptase that has an A-D relationship (also a B_C relationship) described in FIG. 4 described below.
このため表 1に記載のフアルマコフォアの条件 3及び条件 4はヒト ^ トリ プ夕一ゼに対する選択性を発揮する上で重要な条件である。 また、 表 1に記載のフアルマコフォアの条件 3の水素結合受容基は、 好ましく は酸素、 窒素、 硫黄等のへテロ原子、 またはフッ素等の電気陰性度が大きい基で ある。 より好ましくは、 カルポニル酸素、 エーテル酸素、 アルコール酸素、 ィミン窒素等が挙げられる。 Therefore, the conditions 3 and 4 of the pharmacophore described in Table 1 are important conditions for exhibiting selectivity for human ^ trypase. Further, the hydrogen bond accepting group under the condition 3 of the pharmacophore shown in Table 1 is preferably a heteroatom such as oxygen, nitrogen and sulfur, or a group having a high electronegativity such as fluorine. More preferred are carbonyl oxygen, ether oxygen, alcohol oxygen, imine nitrogen and the like.
また、 表 1に記載のフアルマコフォアの条件 4の芳香環もしくは環状炭化水素 の大きさは好ましくは、 ベンゼン環 1個の大きさからベンゼン環 3個が縮環した 大きさである。 より好ましくはベンゼン環 2個が縮環した大きさである。  Further, the size of the aromatic ring or cyclic hydrocarbon under the condition 4 of the pharmacophore described in Table 1 is preferably a size obtained by condensing three benzene rings from one benzene ring. More preferably, the size is such that two benzene rings are condensed.
表 2に記載のフアルマコフォアについて説明する。  The pharmacophore described in Table 2 will be described.
表 2に記載のフアルマコフォアの条件 1及び条件 2は、 表 1に記載のフアルマ コフォアの条件 1及び条件 2の記載の通りである。  The pharmacophore conditions 1 and 2 described in Table 2 are as described in the pharmacophore conditions 1 and 2 described in Table 1.
表 2に記載のフアルマコフォアの条件 3は、 ヒ卜 )3トリプ夕一ゼに特異的 な 9 0番ループとの相互作用を規定する条件である。  The pharmacophore condition 3 described in Table 2 is a condition that regulates the interaction with the loop No. 90 specific to human) 3 trypase.
また、 4量体を形成するトリプタ一ゼにおいて、 当該表 2を満たす化合物は 4 量体に 4個結合する。 隣接するトリプ夕一ゼに結合している 2つの化合物が 2分 子間で相互作用して 1対のペアをなし、 このペアが 2対存在する。 表 2に記載の フアルマコフォアの条件 4は、 隣接する 2つのトリプターゼに結合している 2つ の化合物分子間の相互作用を規定する条件である。 隣接する 2つのトリプターゼ とは、 後述する図 6に記載の A— Dの関係 （B— Cの関係も等価） にあたる 2つ のトリプターゼである。  Further, in the tryptase forming a tetramer, four compounds satisfying the above Table 2 bind to the tetramer. Two compounds that bind to adjacent trypsinase interact between the two molecules to form a pair, and there are two pairs of this pair. The pharmacophore condition 4 described in Table 2 is a condition for defining an interaction between two compound molecules bound to two adjacent tryptases. The two adjacent tryptases are two tryptases corresponding to the relationship A—D (equivalent to the relationship B—C) described in FIG. 6 described below.
このため表 2に記載のフアルマコフォアの条件 3及び条件 4はヒト /3トリ プ夕一ゼに対する選択性を発揮する上で重要な条件である。  Therefore, conditions 3 and 4 of the pharmacophore described in Table 2 are important conditions for exhibiting selectivity for human / 3-triple enzyme.
また、 表 2に記載のフアルマコフォアを満たす分子は、 好ましくは、 もう一方 の分子と、 C 2回転軸を中心に約 1 8 0 回転した位置関係に存在することであ る。 C 2回転軸は、 例えば、 図 7において確認できる 2つの化合物 Bの T— 7Γ相 互作用の中心点を通る、 図 7に対して垂直な軸である。 Further, the molecule satisfying the pharmacophore described in Table 2 is preferably the other molecule. Exists in a positional relationship with the numerator of about 180 rotation about the C2 rotation axis. The C2 axis of rotation is, for example, an axis perpendicular to FIG. 7, passing through the center point of the T-7Γ interaction of the two compounds B identified in FIG.
かかる表 1および表 2に示されるフアルマコフォアは、 ヒト ]3トリプ夕一ゼと 特定のリガンドとの複合体結晶に基づいて初めて導き出されたものである。 特に、 驚くべきことに後述する実施例 4の化合物 Aと化合物 Bとは、 芳香族スル ホンアミドと芳香族アミド （カルポアミド） とのわずかな違いにより、 兀一 π相 互作用の可否並びに酵素への結合モードが全く異なることが確認された。 このこ とは、 トリプ夕一ゼに対する阻害剤について構造活性相関を行っていく上で非常 に重要な知見を与えるものであるが、 ヒト 3トリプターゼの単純結晶のみからか かる事実を導き出すことは困難である。  The pharmacophores shown in Tables 1 and 2 have been derived for the first time based on a complex crystal of human] 3 trypticase and a specific ligand. In particular, surprisingly, the compound A and the compound B of Example 4 described later are different from the aromatic sulfonamide and the aromatic amide (carpoamide) due to the slight difference between the aromatic sulfonamide and the aromatic amide (carpoamide). It was confirmed that the coupling modes were completely different. This provides a very important finding in conducting structure-activity relationships for trypsinase inhibitors, but it is difficult to derive the fact that only simple crystals of human 3-tryptase are involved. It is.
表 1または表 2に記載の条件 1〜4をすベて満たすフアルマコフォアから得ら れる化合物は、 ヒト ]3トリプ夕一ゼに結合する可能性を有する化合物である ため、 ヒト jSトリプ夕一ゼ活性を阻害する化合物となり得る可能性が生じる。 ①の工程は、 表 1または表 2に示すフアルマコフォアをコンピュータ一ソフト ウェアに供用することにより、 前記フアルマコフォアを満たすヒト /3トリプ夕一 ゼ活性を阻害する化合物をバ一チヤルで選択する工程である。 フアルマコフォア から、 新規なトリプターゼ活性を阻害する化合物を選択する工程に関しては、 前 記第一のスクリ一ニング方法に記載された通りである。  A compound obtained from a pharmacophore that satisfies all of the conditions 1 to 4 described in Table 1 or Table 2 is a compound that has a possibility of binding to human] 3 trypase, and therefore, human jS trypase is used. This raises the possibility of becoming a compound that inhibits the activity. Step (1) is a step in which the pharmacophore shown in Table 1 or Table 2 is applied to computer software to select a compound that satisfies the pharmacophore and inhibits human / 3-trippase activity by means of a valley. . The step of selecting a compound that inhibits a novel tryptase activity from the pharmacophore is as described in the first screening method.
表 1または表 2に示すフアルマコフォアはヒト /3トリプターゼと化合物 Aとの 複合体の結晶構造解析またはヒ卜 i3トリプターゼと化合物 Bとの複合体の結晶構 造解析から特定された 該フアルマコフォアを供用してスクリーニングすることができるコン ピュー夕一ソフトウェアは、 コンピュータ一上で蛋白質にリガンドをドッキング させる操作が可能なソフトウエアであれば何を用いても良く、 例えば DOCK (UCSF Sof tware社） 、 Fl exX (トライボス社） 、 L igand Fi t (アクセルリス社 ) 、 Lud i (アクセルリス社） 等を用いてもよい。 例えば、 トリプタ一ゼ活性を阻 害する化合物が相互作用するフアルマコフォアに規定されたアミノ酸残基は、 ヒ ト /3トリプタ一ゼが選択的に結合し得るポケットゃ、 クレーブを提供するので、 該ポケットゃクレーブの情報をソフトウェアに入力して、 コンピュータスクリー ニングを行うことも可能となる。 The pharmacophore shown in Table 1 or Table 2 was identified from the crystal structure analysis of the complex of human / 3 tryptase and compound A or from the crystal structure analysis of the complex of human i3 tryptase and compound B As the computer software that can screen using the pharmacophore, any software can be used as long as it can perform the operation of docking a ligand to a protein on a computer. For example, DOCK (UCSF Software) ), Fl exX (Tribos), Ligand Fit (Accelris), Ludi (Accelris), and the like. For example, an amino acid residue defined in the pharmacophore with which a compound that inhibits tryptase activity interacts provides a pocket that can selectively bind human / 3 tryptase. It is also possible to input the information of the clave into the software and perform computer screening.
以下に DOCKを用いる一例を示す。 まず、 SPHGENプログラムを用いて、 表 1また は表 2のフアルマコフォアより、 トリプタ一ゼ活性を阻害する化合物が結合し得 ると考えられるポケット及びクレープの周囲に対してスフエアと呼ばれる仮想の 球体を配置する。 この球体は、 リガンドをドッキングさせる際のアンカー （錨） として機能する。 なお、 スフエアの発生部位は特定のポケット、 クレーブに限定 することも可能であるし、 複数の部位に発生させることもできる。 発生した スフエアの数が多い際には、 近接するスフエアを手動で除去することも可能であ る。  An example using DOCK is shown below. First, using the SPHGEN program, virtual spheres called spheres were placed around the pockets and crepes, where compounds that inhibit tryptase activity could bind, from the pharmacophores in Table 1 or Table 2. I do. This sphere functions as an anchor when docking the ligand. It should be noted that the location where spheres are generated can be limited to a specific pocket or clave, or can be generated in multiple locations. When the number of generated air is large, it is also possible to remove the adjacent air manually.
次に、 GRIDプログラムを用いてフアルマコフォアを発生させた /3トリプターゼ 分子の領域に対してグリッド （格子） を発生させ、 指定された範囲の受容体残基 における電子的及び立体的な環境を、 各グリッド上のスカラー値として表 現する。 なお、 各グリッドの値を算出するために AMBER等の力場を本発明者等は 利用したが、 他の力場を使用してもよく、 必ずしも AMBER に限定するものではな P T/JP2003/009738 Next, a grid was generated for the region of the / 3 tryptase molecule that generated the pharmacophore using the GRID program, and the electronic and steric environment at the specified range of receptor residues was determined. Expressed as a scalar value on the grid. Although the present inventors used a force field such as AMBER to calculate the value of each grid, other force fields may be used, and the present invention is not necessarily limited to AMBER. PT / JP2003 / 009738
4 1 レ また、 蛋白質側の形状によっては、 グリッド情報を改変し、 化合物の ドッキングがより現実に近い形で表現されるように調節することも可能で ある。  Depending on the shape of the protein side, it is also possible to modify the grid information so that the docking of the compound is expressed in a more realistic form.
あらかじめ準備したコンピュータスクリーニング用の化合物構造データベース を対象としてスクリーニングを実施する。 コンピュータスクリーニングの利点と して、 検索対象が理論上考え得る全ての化合物の部分集合であることが挙げられ る。 通常は、 自社で保有する化合物のデータベース、 市販化合物データべ一ス、 例えば Avai l abl e Chemicals Di rec tory (MDL 社） や各化合物販売会社 ·代理店 が作成したデータベース、 もしくはバーチャルコンビナトリアル合成手法等を用 いて発生させた仮想化合物のデータベース、 天然物由来の化合物データベース、 医薬品データベース等をコンピュータ検索用に変換して用いる。 化合物 データベースの検索には、 DOCKプログラムを用いて、 ポケット及びクレーブの周 囲に存在するスフエアの近傍に位置し、 かつ、 グリッド上の立体的要素、 あるい は電子的要素と反発しないような 3次元配座を取るような化合物を探索する。 こ の際、 ドッキングされた化合物の 3次元配座は、 DOCKプログラムに内蔵された配 座発生機能により最適化されるが、 最終的に適切なドッキングが行われたかどう かは、 ドッキング時のスコア、 目視等によって経験的な判断を加味してフアルマ コフォアへの合致を確認しヒッ ト化合物を決定する。 このようにして適切な ドッキングが行われていると判断された一連のヒット化合物群は、 ヒト ]3トリプ 夕ーゼ活性を選択的に阻害する化合物の候補として、 一定の確率でヒト 0 トリプ ターゼ活性を選択的に阻害する。  Screening is performed on a prepared compound structure database for computer screening. The advantage of computer screening is that the search target is a subset of all theoretically possible compounds. Usually, a database of compounds owned by the company, a database of commercially available compounds, such as Avaliable Chemicals Directory (MDL), a database created by each compound sales company and agency, or a virtual combinatorial synthesis method The database of virtual compounds generated using the database, the database of compounds derived from natural products, and the database of pharmaceuticals are converted and used for computer search. The compound database is searched using the DOCK program, which is located in the vicinity of the space around the pocket and clave and does not repel the three-dimensional or electronic elements on the grid. Search for compounds that adopt a dimensional conformation. At this time, the three-dimensional conformation of the docked compound is optimized by the conformation generation function built into the DOCK program.However, whether the docking was properly performed is determined by the score at the time of docking. Considering the empirical judgment by visual observation, etc., the conformity to the pharmacophore is confirmed, and the hit compound is determined. A series of hit compounds determined to be properly docked in this way are human 0 tryptase with a certain probability as candidates for compounds that selectively inhibit human] 3 trypase activity. Selectively inhibits activity.
また、 フアルマコフォアを供用してスクリーニングすることができるコン ピュー夕一ソフトウェアは、 コンピュータ一上でリガンドからの化学的機能の抽 出および抽出した化学的機能と類似した空間配置を取り得る化合物の検索が可能 なソフトウェアであれば何を用いても良く、 例えば Catalyst (アクセルリス 社） 、 Sybyl (トライボス社） のモジュールである Unity等を用いてもよい。 以下に Catalystを用いる一例を示す。 表 1または表 2のフアルマコフォアを用 いて、 化学的機能の 3次元空間上における相対的な位置関係を設定すること によって、 Catalyst上の検索式 （フアルマコフォア） が作成可能である。 なお、 規定の方法は、 座標 （x,y，z ) による規定でも、 各点を結ぶ直線距離の集合によ る規定であっても構わない。 また、 実際に受容体と相互作用可能な距離、 計算上 の誤差等を考慮にいれると、 各々の化学的機能の距離関係は必ずしも厳密である 必要はない。 Catalystでは各化学的機能の位置は、 各点を中心とした半径 1.5〜 2.0 Aの球内、 もしくは、 各点を結ぶ直線距離 ± 3〜4人の範囲によって定義さ れるのが一般的であるが、 この数値は適宜変更することもできる。 In addition, a consortium capable of screening using a pharmacophore Any software can be used as long as it can extract chemical functions from ligands and search for compounds that can take a spatial configuration similar to the extracted chemical functions on the computer. For example, a module such as Catalyst (Accelris) or Sybyl (Tribos) may be used. An example using Catalyst is shown below. By using the pharmacophores in Table 1 or Table 2 to set the relative positions of chemical functions in three-dimensional space, it is possible to create a search formula (pharmacophore) on Catalyst. The specified method may be specified by coordinates (x, y, z) or by a set of linear distances connecting each point. Also, taking into account the distance that can actually interact with the receptor, calculation errors, etc., the distance relationship between the chemical functions does not necessarily have to be strict. In Catalyst, the position of each chemical function is generally defined by a sphere with a radius of 1.5 to 2.0 A centered on each point, or a linear distance connecting each point ± 3 to 4 people However, this value can be changed as appropriate.
あらかじめ準備したコンピュータスクリーニング用の化合物構造デ一夕ベース を対象としてスクリーニングを実施する。 コンピュータ一スクリーニングの利点 として、 検索対象が理論上考え得る全ての化合物の部分集合であることが挙げら れる。 通常は、 自社で保有する化合物のデータベース、 市販化合物データ ベース、 例えば Available Chemicals Directory (MDL社） や各化合物販売会社 •代理店が作成したデータべ一ス、 もしくはバーチャルコンビナトリアル合成手 法等を用いて発生させた仮想化合物のデータベース、 天然物由来の化合物データ ベース、 医薬品デ一タベース等をコンピュータ検索用に変換して用いる。  Screening is performed on a compound screening database prepared in advance for computer screening. The advantage of computer-based screening is that the search target is a subset of all theoretically possible compounds. Normally, a database of compounds owned by the company or a commercially available compound database, such as the Available Chemicals Directory (MDL) or each compound sales company • Using a database created by a distributor or a virtual combinatorial synthesis method, etc. A database of generated virtual compounds, a database of compounds derived from natural products, and a database of pharmaceuticals are converted and used for computer search.
上記コンピュータスクリーニングによりヒッ卜した化合物群は、 記述のフアル P T/JP2003/009738 Compounds hit by the above computer screening are listed in the description file. PT / JP2003 / 009738
4 3  4 3
マコフォアに結合する可能性を有する化合物であるため、 選択的にヒト /3トリプ 夕ーゼ活性を阻害する化合物となり得る可能性が、 一定の確率で発生する。 さら に実際のアツセィでのヒット率を増すために、 ヒト 3トリプターゼの結晶構造分 子自体を排除体積として利用することもできるし、 化合物 Aまたは、 化合物 Bの 活性コンフオメーシヨンの分子形状を表す検索式 （シエイプ） を作成し、 先に作 成したフアルマコフォアとマージすることにより、 ヒト ]3トリプターゼ活性を選 択的に阻害する化合物の分子形状を有し、 つ、 化学的機能においてもその条件 を満たし得る検索式で規定された相対的空間配置を満たす化合物を検索すること も可能である。 また、 これらの検索式でヒットした化合物群をデータベース 化し、 引き続き蛋白質構造への市販のドッキングソフトウェアに適用することに よってヒット率を増すこともできる。 Since the compound has the potential to bind to the macophore, there is a certain probability that it can be a compound that selectively inhibits human / 3-tripse activity. To further increase the actual hit rate in Atsushi, the crystal structure molecule of human 3 tryptase itself can be used as the excluded volume, and it represents the molecular shape of the active conformation of Compound A or Compound B By creating a search formula (shape) and merging it with the pharmacophore created earlier, it has the molecular shape of a compound that selectively inhibits human] 3 tryptase activity, and the conditions for chemical functions It is also possible to search for a compound that satisfies the relative spatial configuration defined by a search formula that can satisfy the following. In addition, it is possible to increase the hit rate by creating a database of compound groups hit by these search formulas and then applying the database to commercially available docking software for protein structures.
第二のスクリーニング方法は、 さらに以下の工程を含むことが好ましい。  It is preferable that the second screening method further includes the following steps.
②①でバーチャルで選択した化合物をリアルで用意する工程、 及び  (2) The process of preparing the compound selected virtually in (1) in real time, and
③②で用意した化合物のトリプ夕一ゼ活性に対する影響を i n V i t roの系および Zまたは in vivo の系にて測定する工程。  (3) a step of measuring the effect of the compound prepared in (1) on tryptic enzyme activity using an in Vitro system and a Z or in vivo system.
②の工程は、 ①で選択した候補化合物を用意する工程であり、 ③の工程は、 ② で用意した候補化合物のトリプターゼ活性に対する影響を測定する工程である。 ②及び③の工程は前記第一のスクリーニング方法に記載された通りである。 また、 ②の工程を複数の化合物について行うことにより、 ヒト /3トリプターゼ 活性を選択的に潜在的に阻害しうる化合物からなる、 後述する第八の態様の化合 物ァレイを作成することができる。  Step (2) is a step of preparing the candidate compound selected in (1), and step (3) is a step of measuring the effect of the candidate compound prepared in (2) on tryptase activity. Steps (2) and (3) are as described in the first screening method. In addition, by performing step (2) on a plurality of compounds, a compound array according to an eighth embodiment described later, comprising a compound capable of selectively and potentially inhibiting human / 3 tryptase activity, can be prepared.
. 本発明の第七の態様は、 以下の工程を含むことを特徴とするヒト /3 トリプ ターゼ活性を選択的に阻害する化合物のドラッグデザィン方法である。 A seventh aspect of the present invention provides a human / 3 trip comprising the following steps: This is a drug design method for a compound that selectively inhibits the enzyme activity.
①表 1に記載のフアルマコフォアの各条件に対応する官能基を有する 各フラグメント群を作成する工程。  (1) A process of preparing each fragment group having a functional group corresponding to each condition of the pharmacophore described in Table 1.
②①で作成した各フラグメント群より一つずつ選択された各フラグメントを 結合させて、 化合物をモデル構築する工程。  (2) A process in which each fragment selected from each fragment group created in (1) is combined to construct a compound model.
また、 以下の工程を含むことを特徴とするヒト /3トリプターゼ活性を選択的に 阻害する化合物のドラッグデザィン方法である。  Also, there is provided a drug design method for a compound which selectively inhibits human / 3 tryptase activity, which comprises the following steps.
①表 2に記載のフアルマコフォアの各条件に対応する官能基を有する各フラ グメント群を作成する工程。  (1) A process for preparing each fragment group having a functional group corresponding to each condition of the pharmacophore described in Table 2.
②①で作成した各フラグメント群より一つずつ選択された各フラグメントを 結合させて、 化合物をモデル構築する工程。  (2) A process in which each fragment selected from each fragment group created in (1) is combined to construct a compound model.
①の工程は、 表 1または表 2に示すフアルマコフォアの各条件に対応する官能 基を有するフラグメント群を作成する工程である。 例えば、 一つのフアルマ コフォアの条件に相当する官能基を有するフラグメントを収集し、 フラグメント 群とする。 また別のフアルマコフォアの条件に相当する官能基を有するフ ラグメントを収集し、 フラグメント群とする。 このようにして、 各条件に相当す る官能基を有する各フラグメント群を作成する。 この時複数のフアルマコフォア を満たす官能基を有するフラグメント、 若しくはフアルマコフォアを満たす官能 基ともう一つのフアルマコフォアを満たす官能基を同時に有するフラグメントを 収集してもよい。 フラグメントの収集の仕方は特に限定するものではない。 例え ば、 既知のトリプターゼ活性を阻害する化合物からフラグメントを収集してもよ い。 収集した一つのフラグメントに置換基をつける、 炭素鎖を伸張若しくは縮減 する、 原子を置換する等により、 新たなフラグメントを作成してもよい。 このと きには、 既知のトリプ夕一ゼ活性を阻害する化合物を改善するようなフラグメン 卜の作成がより有用である。 例えば、 トリプ夕一ゼとトリプ夕一ゼ活性を阻害す る化合物間に存在する水分子 （構造水） も、 両者の複合体形成に役割を果たすこ とがあり、 これを介した蛋白質—トリプターゼ活性を阻害する化合物間の相互作 用は、 グラフィックス観察などによって特定できる。 更に、 相互作用可能なアミ ノ酸残基や水分子のうち、 特に、 疎水的な相互作用 ·イオン結合 '水素結合を形 成している部位やアミノ酸残基、 更には、 複合体構造のトリプ夕一ゼ活性を阻害 する化合物の活性コンフオメーションが与える分子形状を解析することよって観 察できる。 このようにして、 既知化合物と近傍のアミノ酸残基との相互作用を増 強させるような誘導の方向性を見出したり、 または、 活性には影響を与えずに、 代謝、 毒性などの改善を進める上で適当な方向性を提示するための新たなフラグ メントの創作が可能である。 Step (1) is a step for preparing a fragment group having a functional group corresponding to each condition of the pharmacophore shown in Table 1 or Table 2. For example, fragments having a functional group corresponding to the condition of one pharmacophore are collected to form a fragment group. In addition, fragments having a functional group corresponding to the conditions of another pharmacophore are collected and used as a fragment group. Thus, each fragment group having a functional group corresponding to each condition is created. At this time, a fragment having a functional group satisfying a plurality of pharmacophores, or a fragment having a functional group satisfying a pharmacophore and a functional group satisfying another pharmacophore simultaneously may be collected. The method of collecting fragments is not particularly limited. For example, fragments may be collected from known compounds that inhibit tryptase activity. Add a substituent to one collected fragment, extend or reduce the carbon chain A new fragment may be created by substituting or replacing an atom. In this case, it is more useful to create a fragment that improves a compound that inhibits a known trypasease activity. For example, a water molecule (structural water) present between trypticase and a compound that inhibits trypticase activity may also play a role in the formation of a complex between the two. Interaction between compounds that inhibit the activity can be identified by, for example, graphics observation. Furthermore, among the amino acid residues and water molecules that can interact with each other, in particular, the sites and amino acid residues that form hydrophobic interactions, ionic bonds, and hydrogen bonds. It can be observed by analyzing the molecular shape given by the active conformation of the compound that inhibits the activity. In this way, the direction of induction that enhances the interaction between a known compound and a nearby amino acid residue is found, or the metabolism, toxicity, etc. are improved without affecting the activity. It is possible to create a new fragment to indicate the appropriate direction above.
表 1または表 2に記載のフアルマコフォアの各条件に対応する官能基を有する フラグメント群を作成する例を下記に示す。  Examples of preparing a fragment group having a functional group corresponding to each condition of the pharmacophore described in Table 1 or Table 2 are shown below.
分子設計を実施するに当たり、 まず表 1または表 2に示したフアルマコフォア に合致する化合物の一般式を作成し、 下記のように表現する。  When conducting molecular design, first formulate a general formula for a compound that matches the pharmacophore shown in Table 1 or Table 2, and express it as follows.
一般式 S i—L— Ar General formula S i—L— Ar
また、 各フラグメントの条件を以下のように設定する。  The conditions for each fragment are set as follows.
フラグメント は、 ヒト j3 トリプターゼ S 1ポケットに結合するフラグ メントであり、 例えば、 Aspl 89の力ルポキシル基と相互作用可能な （好ましくは イオン結合可能な） 窒素原子を有する置換基をもつあるいは環構造に窒素を含む 芳香環もしくは当該置換基をもつ環状炭化水素を部分構造として含むフラグ メント。 リンカ一への結合を想定して、 アルキレン基、 アミノ基、 力ルポニル基 等が、 フラグメント基部に存在していることが好ましい。 このフラグメントは更 にハロゲン、 炭素数 1〜 3のアルキル基、 アルコキシル基若しくはチォアルキル 基、 カルボキシル基、 または炭素数 2〜 4のァシル基若しくはカルポキシアルキ ル基などで置換されていても良い。 A fragment is a fragment that binds to the human j3 tryptase S1 pocket and has, for example, a substituent or a ring structure that has a nitrogen atom capable of interacting (preferably ionically) with the hapoxyl group of Aspl 89. Contains nitrogen A fragment containing, as a partial structure, an aromatic ring or a cyclic hydrocarbon having the substituent. Assuming a bond to a linker, it is preferable that an alkylene group, an amino group, a sulfonyl group, and the like be present in the fragment base. This fragment may be further substituted with a halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxyl group or a thioalkyl group, a carboxyl group, or an acyl group or a carboxyalkyl group having 2 to 4 carbon atoms.
フラグメント Lは と A rの双方を連結するフラグメントであり、 フアルマ コフォアに合致する分子の立体配座を維持できるもの。 例えば、 リンカ一内 部に、 窒素、 酸素、 硫黄から選ばれるヘテロ原子 1個ないし 3個 （好ましくは窒 素原子 1個ないし 2個） および炭素数 1個ないし 5個を有する直鎖もしくは環状 の炭化水素基が挙げられる。 当該炭化水素基は、 更に、 炭素数 1〜3のアルキル 基、 アルコキシル基、 チォアルキル基若しくはアルキルスルホニル基、 カルポキ シル基、 または炭素数 2〜4のァシル基若しくはカルボキシアルキル基またはォ キソ基等の置換基を有していても良い。 リンカ一の端部は、 S 1および A rのフ ラグメン卜への結合を想定して、 イミノ基、 アルキレン基、 カルボニル基である ことが好ましい。  Fragment L is a fragment that connects both and Ar, and can maintain the conformation of the molecule that matches the pharmacophore. For example, a linear or cyclic structure having 1 to 3 hetero atoms (preferably 1 to 2 nitrogen atoms) and 1 to 5 carbon atoms selected from nitrogen, oxygen and sulfur in the linker. And hydrocarbon groups. The hydrocarbon group further includes an alkyl group having 1 to 3 carbon atoms, an alkoxyl group, a thioalkyl group or an alkylsulfonyl group, a carboxyl group, or an acyl group, a carboxyalkyl group, or an oxo group having 2 to 4 carbon atoms. It may have a substituent. The end of the linker is preferably an imino group, an alkylene group, or a carbonyl group, assuming the binding of S1 and Ar to the fragment.
フラグメント A rは芳香環または環状炭化水素を基本構造に持つフラグメント である。 好ましくは、 構成員数 5ないし 1 4の単環、 縮環もしくは縮合 3環を有 し、 環内に窒素、 酸素、 硫黄などのへテロ原子が含まれていても良い。 特に好ま しくはナフ夕レン環などの 2環性芳香環である。 リンカ一への結合を想定して、 スルホニル基、 カルボニル基、 アルキレン基等がフラグメント基部に存在してレ ることが好ましい。 また芳香環または環状炭化水素はハロゲン、 炭素数 1〜3の T JP2003/009738 Fragment Ar is a fragment having an aromatic ring or a cyclic hydrocarbon as its basic structure. It preferably has a monocyclic, condensed or condensed tricyclic ring having 5 to 14 members, and may contain a heteroatom such as nitrogen, oxygen, or sulfur in the ring. Particularly preferred is a bicyclic aromatic ring such as a naphthylene ring. It is preferable that a sulfonyl group, a carbonyl group, an alkylene group, and the like be present in the fragment group, assuming a bond to a linker. In addition, aromatic rings or cyclic hydrocarbons are halogen, having 1 to 3 carbon atoms. T JP2003 / 009738
4 7  4 7
アルキル基、 アルコキシル基若しくはチォアルキル基、 力ルポキシル基、 炭素数 2〜4のァシル基若しくはカルポキシアルキル基、 ォキソ基またはアミノ基など で置換されていても良い。 It may be substituted by an alkyl group, an alkoxyl group or a thioalkyl group, a propyloxyl group, an acyl group or a carboxyalkyl group having 2 to 4 carbon atoms, an oxo group or an amino group.
作成したフラグメン.ト群の例を後述する実施例 7の記載の表 3及び表 4に示し た。  Examples of the prepared fragment groups are shown in Tables 3 and 4 described in Example 7 described later.
フラグメント S i は、 表 3に記載のフラグメント S i に、 更にハロゲン、 炭素 数 1〜3のアルキル基、 アルコキシル基若しくはチォアルキル基、 力ルポキシル 基、 または炭素数 2〜 4のァシル基若しくはカルポキシアルキル基などで置換さ れるフラグメントでもよい。  The fragment S i is the same as the fragment S i shown in Table 3 except that halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxyl group or a thioalkyl group, a lipoxyl group, or an acryl group or a carboxyalkyl group having 2 to 4 carbon atoms. It may be a fragment substituted with a group or the like.
フラグメント Lは、 表 3に記載のフラグメント Lに、 更に炭素数 1〜3の アルキル基、 アルコキシル基、 チォアルキル基若しくはアルキルスルホニル基、 力ルポキシル基、 または炭素数 2〜 4のァシル基若しくはカルボキシアルキル基 またはォキソ基等の置換基を有していてもよい。 更にまた、 表 3に記載の フラグメント Lの炭素水素基の炭素が、 さらに窒素、 酸素、 硫黄から選ばれるへ テロ原子 1個ないし 2個に置換されていてもよい。 この場合、 フラグメント の 総へテロ原子として、 窒素原子は 1個または 2個が好ましい。  Fragment L is the same as fragment L shown in Table 3, except that it further has an alkyl group having 1 to 3 carbon atoms, an alkoxyl group, a thioalkyl group or an alkylsulfonyl group, a carbonyl group, or an acryl group or a carboxyalkyl group having 2 to 4 carbon atoms. Alternatively, it may have a substituent such as an oxo group. Furthermore, the carbon of the hydrocarbon group of fragment L shown in Table 3 may be further substituted with one or two hetero atoms selected from nitrogen, oxygen and sulfur. In this case, the total number of nitrogen atoms in the fragment is preferably one or two.
フラグメント A rは、 表 4に記載のフラグメント A rの芳香環または環状炭化 水素に、 更にハロゲン、 炭素数 1〜3のアルキル基、 アルコキシル基若しくはチ ォアルキル基、 カルボキシル基、 炭素数 2〜4のァシル基若しくは力ルポキシァ ルキル基、 ォキソ基またはアミノ基などで置換されていても良い。 更にまた、 表 4に記載のフラグメント A rの芳香環または環状炭化水素は、 窒素、 酸素、 硫黄 などのへテロ原子が含まれていても良い構成員数 5ないし 1 4の別の単環、 縮環 もしくは縮合 3環で置き換わっていてもよい。 好ましくは芳香環または環状炭化 水素が、 ナフタレン環、 ベンゾチォフェン環などの 2環性芳香環で置き換わった フラグメントである。 Fragment Ar is obtained by adding a halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxyl group or a thioalkyl group, a carboxyl group, a C 2-4 carbon atom to the aromatic ring or cyclic hydrocarbon of the fragment Ar shown in Table 4. It may be substituted with an acyl group, a carbonyloxy group, an oxo group or an amino group. Furthermore, the aromatic ring or cyclic hydrocarbon of the fragment Ar shown in Table 4 is a different monocyclic or condensed 5- to 14-membered member which may contain a heteroatom such as nitrogen, oxygen or sulfur. ring Alternatively, it may be replaced by a condensed three ring. Preferably, a fragment in which an aromatic ring or a cyclic hydrocarbon is replaced by a bicyclic aromatic ring such as a naphthalene ring or a benzothiophene ring.
また、 表 2に記載のフアルマコフォアを用いることにより、 隣接する トリプ夕ーゼの 2分子に対して、 同一化合物 2分子で阻害することを規定して、 ドラッグデザィンをすることもできる。 例えば、 一方の化合物が一方の卜リ プタ一ゼの S 1ポケットに結合し、 もう一方の化合物がもう一方のトリプターゼ の S 1ポケットに結合する。 そして、 化合物に芳香族アミド基を有させることに より、 化合物同士が — π相互作用をすることを規定するドラッグデザィンであ る。 隣接するトリプ夕ーゼとは、 後述する図 4に記載の A— Dの関係 （Β— Cの 関係も等価） にあたるトリプ夕一ゼである。  In addition, by using the pharmacophore described in Table 2, it is possible to perform drug design by defining that two molecules of the adjacent trypase are inhibited by two molecules of the same compound. For example, one compound binds to the S1 pocket of one tryptase and the other compound binds to the S1 pocket of the other tryptase. And it is a drug design that specifies that compounds have an —π interaction by giving the compounds an aromatic amide group. The adjacent trypase is a trypase that corresponds to the relationship A to D (the relationship of Β to C) described in FIG. 4 described below.
②の工程は、 ①で作成したフラグメント群より一つずつ選択された各フラグメ ントを結合させて、 化合物をモデル構築する工程である。 例えば、 紙上において ①で決定した各フラグメント群より一つずつ選択された各フラグメントを結合さ せて、 化合物をモデル構築してもよい。 好ましくはコンピューターソフトウェア を用いて化合物をモデル構築することである。 用いるソフトウェアは、 化合物の 構造構築可能なソフトウェアであれば何を用いても良く、 例えば Ludi (アクセル リス社） または Sybyl (トライポス社） のモジュールである Comb iLibMaker 等を 用いてもよい。 コンピュータ一ソフトウェアを用いて化合物をモデル構築するこ とにより、 短時間で数多くのモデル構築をすることができるばかりでなく、 ③の 工程に供用する時にも便利である。  Step (2) is a step of combining the fragments selected one by one from the fragment group created in (1) to construct a compound model. For example, a compound model may be constructed by combining fragments selected one by one from each fragment group determined in 1) on paper. Preferably, the compound is modeled using computer software. Any software may be used as long as it can construct the structure of the compound. For example, CombiLibMaker, a module of Ludi (Accelris) or Sybyl (Tripos), may be used. By constructing a model of a compound using computer software, not only can a large number of models be constructed in a short time, but it is also convenient when the compound is used in the process of (3).
好ましくは、 表 3及び表 4に記載の各フラグメント群より選択された各フラグ メントを結合させて、 化合物をモデル構築する工程である。 Preferably, each flag selected from each fragment group described in Tables 3 and 4 This is the step of building a model of the compound by binding the components.
フラグメントを結合させるとは、 フラグメント同志を直接結合させること、 及 びフラグメントの間にリンカ一を用いることにより、 リンカ一を解して結合させ ることが含まれる。 リンカ一は特に限定されない。 例えば、 直鎖若しくは側鎖を 有する炭化水素の基、 前記炭化水素の基がヘテロ化合物で置換された基等が挙げ られる。  Binding fragments includes directly binding the fragments, and using a linker between the fragments to release the linker and bind the fragments. The linker is not particularly limited. Examples thereof include a hydrocarbon group having a straight chain or a side chain, and a group in which the hydrocarbon group is substituted with a hetero compound.
さらに本発明のドラッグデザィンの方法は、 以下の工程を含むことが好ま しい。  Further, the method for drug design of the present invention preferably includes the following steps.
③上記フアルマコフォアをコンピューターソフトウエアに供用することに より、 ②でモデル構築した化合物のうち、 ヒト i3トリプ夕ーゼ活性を選択的に阻 害する化合物を選択する工程。  (3) A step in which the above-mentioned pharmacophore is applied to computer software to select a compound that selectively inhibits human i3 trypsinase activity among the compounds constructed in (2).
③の工程は、 上記フアルマコフォアをコンピューターソフトウェアに供用する ことにより、 ②でモデル構築した化合物のうち、 ヒト iSトリプタ一ゼ活性を選択 的に阻害する化合物を選択する工程である。 すなわち、 ②でモデル構築した化合 物群をデ一夕ベースとして、 本発明の第六の態様で説明された通り、 コンビユー 夕一ソフトウェアに供用して、 化合物を選択する工程である。 このように選択し たヒト i3トリプタ一ゼ活性を選択的に、 潜在的に阻害する （阻害する可能性を持 つ） 化合物の集合をライブラリ一として、 新規なヒト ]3トリプ夕一ゼ活性を阻害 する化合物のスクリーニングに用いることができる。 該ライブラリ一は一般 のデータベースと比較して、 ヒト ]3トリプターゼ阻害活性をかなり高い確率で有 する化合物の集合である。  Step (3) is a step of using the above-mentioned pharmacophore for computer software to select a compound that selectively inhibits human iS tryptase activity among the compounds constructed in (2). In other words, as described in the sixth embodiment of the present invention, the compound group modeled in (2) is used for the combination software as described in the sixth embodiment of the present invention to select a compound. The selected human i3 tryptase activity is selectively and potentially inhibited (possibly inhibited) as a library. It can be used to screen for compounds that inhibit it. The library 1 is a set of compounds having a human] 3 tryptase inhibitory activity with a considerably higher probability than a general database.
本発明のドラッグデザィン方法はさらに以下の工程を含めて、 ヒト β トリプ夕一ゼ活性を選択的に阻害する化合物のスクリ一二ングを "ることが好ま しい。 The drug design method of the present invention further comprises the following steps: It is preferable to screen for compounds that selectively inhibit tripase activity.
④②の工程でバーチャルで構築した化合物をリアルで用意する工程、 及び The process of preparing the compound constructed in virtual in step ④② in real time, and
⑤用意した前記候補化合物のトリプタ一ゼ活性に対する影響を in vi troの系お よび/または in vivoの系にて測定する工程。 (4) A step of measuring the effect of the prepared candidate compound on tryptase activity in an in vitro system and / or an in vivo system.
④、 ⑤の方法は本発明の第六の態様に説明された通りである。  The methods (1) and (2) are as described in the sixth embodiment of the present invention.
本スクリーニング方法を用いることにより、 ランダム化合物を用いて、 ヒト /3 トリプ夕ーゼ活性に対する影響をスクリーニングするよりも、 ヒット化合物の確 率が高くなる。  By using this screening method, the probability of hit compounds is higher than screening the effect on human / 3 trypsinase activity using a random compound.
さらに上記①〜⑤の工程を含めて、 ヒト )3トリプターゼ活性を選択的に阻害す る化合物のスクリーニングをすることが好ましい。 この場合、 ④の工程は、 ③の 工程で選択した化合物を用意する工程、 となる。  Further, it is preferable to screen for a compound that selectively inhibits human) 3 tryptase activity, including the above steps (1) to (4). In this case, step (2) is a step of preparing the compound selected in step (3).
また、 本発明のドラッグデザィンの方法は、 ②の工程及び③の工程を同時に行 うことができる。 ②の工程において、 選択したフラグメントをコンピュータ一上 で結合させる際に、 フアルマコフォアを該コンピュータ一に供用して、 フアルマ コフォアを満たす結合をさせることにより、 化合物モデルを構築すればよい。 こ の場合、 コンピューターソフトウエアにフアルマコフォアを供用してもよい。 ま たフアルマコフォアを満たすような結合をさせることが可能なように、 プロダラ ムを設計してもよい。  In the method of drug design of the present invention, the steps (2) and (3) can be performed simultaneously. In the step (2), when the selected fragments are combined on a computer, a compound model may be constructed by applying the pharmacophore to the computer and binding the pharmacophore. In this case, a pharmacophore may be provided to the computer software. In addition, the program may be designed so that a bond that satisfies the pharmacophore can be formed.
また、 ④の工程を複数の化合物について行うことにより、 後述する第八の態様 で説明するヒト )3トリプ夕一ゼ活性を選択的に潜在的に阻害しうる化合物からな る化合物ァレイを作成することができる。 本発明の第八の態様は、 ヒト jSトリプ夕ーゼ活性を選択的に潜在的に阻害しう る化合物からなる化合物アレイの作成方法であり、 表 1に記載のフアルマコフォ ァをコンピュータ一ソフトウエアに供用することにより前記フアルマコフォアを 満たすヒト ]3 トリプタ一ゼ活性を選択的に阻害する化合物をバーチャルで 選択し、 選択した化合物を実際にリアルで用意して組み合わせて化合物アレイを 作成する方法である。 In addition, by performing the step (2) for a plurality of compounds, a compound array consisting of a compound capable of selectively and potentially inhibiting human) tripsease activity described in an eighth embodiment described below is prepared. be able to. An eighth aspect of the present invention is a method for preparing a compound array comprising a compound capable of selectively and potentially inhibiting human jS trypsinase activity, wherein the pharmacophore described in Table 1 is prepared by computer-software. A human that satisfies the above-mentioned pharmacophore by applying to a human) 3) A compound array that is prepared by virtually selecting compounds that selectively inhibit tryptase activity, and then preparing and combining the selected compounds in real life. .
また、 ヒト トリプタ一ゼ活性を選択的に潜在的に阻害しうる化合物からなる 化合物アレイの作成方法であり、 表 2に記載のフアルマコフォアをコン ピュ—夕一ソフトウェアに供用することにより前記フアルマコフォアを満た すヒト トリプタ一ゼ活性を選択的に阻害する化合物をバーチャルで選択し、 選 択した化合物を実際にリアルで用意して組み合わせて化合物アレイを作成する方 法である。  Also, the present invention relates to a method for preparing a compound array comprising a compound capable of selectively and potentially inhibiting human tryptase activity, wherein the pharmacophore described in Table 2 is used for computer software to satisfy the pharmacophore. In this method, compounds that selectively inhibit human tryptase activity are virtually selected, and the selected compounds are actually prepared in real life and combined to form a compound array.
潜在的に阻害しうる化合物とは、 理論的には阻害する化合物であり、 実際の in vi tro及び Zまたは in vivo の試験において、 ランダム化合物よりも高い確率で 阻害する可能性を有する化合物である。 本発明の化合物アレイの作成方法におい て作成される化合物は、 すなわち表 1若しくは表 2のフアルマコフォアの条件を 満たす化合物であるので、 理論的には阻害する化合物である。  A potentially inhibitory compound is a compound that theoretically inhibits and that has a higher probability of inhibition than a random compound in actual in vitro and Z or in vivo tests. . The compound prepared by the method for preparing a compound array of the present invention is a compound that satisfies the pharmacophore conditions shown in Table 1 or Table 2, and is therefore a compound that theoretically inhibits.
本発明の作成方法は、 既存の化合物アレイ、 若しくは作成中の化合物 アレイに、 新たに化合物を追加する方法も含まれる。  The preparation method of the present invention includes a method of adding a new compound to an existing compound array or a compound array being prepared.
化合物アレイとは、 in vi tro及び/または in v ivo試験に供用されるように用 意された、 実際のリアルの化合物の集合である。 通常、 プレート等の支持体に保 持されるものである。 例えばスクリーニングプレート、 並べられたサンプル チューブ等が挙げられる。 A compound array is a collection of real, real compounds prepared for in vitro and / or in vivo testing. Usually, it is held on a support such as a plate. For example, screening plates, aligned samples Tubes and the like.
本発明の作成方法は本発明の第六の態様及び第七の態様の説明の通りである。 好ましくは、 表 3及び表 4に記載のフラグメント群より一つずつを選択し、 選 択したフラグメントを結合させて、 化合物をモデル構築する工程を含むドラッグ デザイン方法を含むである化合物アレイの作成方法である。  The production method of the present invention is as described in the sixth and seventh aspects of the present invention. Preferably, a method of preparing a compound array, which includes a drug design method including a step of selecting one fragment from each of the fragment groups described in Tables 3 and 4 and binding the selected fragments to construct a compound model It is.
本発明の作成方法で作成した化合物アレイは、 ヒト JS トリプターゼ活性を選択 的に潜在的に阻害しうる化合物からなるため、 従来のランダムな化合物を含む化 合物アレイより、 ヒト i3トリプターゼ活性を選択的に阻害する化合物をかなり高 い確率で得ることができる。  Since the compound array prepared by the preparation method of the present invention is composed of compounds that can selectively inhibit human JS tryptase activity, human i3 tryptase activity is selected from a conventional compound array containing random compounds. Compounds that inhibit the activity can be obtained with a considerably high probability.
本発明の第九の態様は、 本発明の第七の態様のスクリーニング方法で作成して 得られるヒト |3 卜リブ夕ーゼ活性を選択的に潜在的に阻害しうる化合物の ライブラリ一である。 具体的には表 3及び表 4に示すフラグメント群より構築し た一般式 S , 一 L一 A rの化合物化合物のデ一夕ベースを、 表 1または表 2に示 すフアルマコフォアをコンピューターソフトウェアに供用することにより得られ る、 ヒト /3 トリプタ—ゼ活性を選択的に潜在的に阻害しうる化合物のライブ ラリーである。  A ninth aspect of the present invention is a library of compounds capable of selectively and selectively inhibiting human | 3 tri-ribose activity obtained by the screening method of the seventh aspect of the present invention. . Specifically, the database of the compound of general formula S, 1L-1Ar constructed from the fragment groups shown in Tables 3 and 4 was used for computer software, and the pharmacophore shown in Table 1 or Table 2 was used. This is a library of compounds that can selectively and potentially inhibit human / 3 tryptase activity.
ライブラリーとは、 通常、 蛋白の推定リガンド若しくは活性を阻害する 化合物、 活性化する化合物等の化合物の混合物または集合体 （群） を意味し、 想 定された概念でくくられる複数の化合物を指す。 本発明のライブラリ一は、 コンビュ一タースクリーニングにより得られるヒト i3トリプターゼ活性を選択的 に潜在的に阻害しうる化合物の集合体である。  A library generally refers to a mixture or aggregate (group) of compounds, such as compounds that inhibit a putative ligand or activity of a protein, and compounds that activate a compound, and refers to a plurality of compounds enclosed by an envisioned concept. . The library 1 of the present invention is a collection of compounds that can selectively and selectively inhibit human i3 tryptase activity obtained by computer screening.
表 3及び表 4に示すフラグメント群より構築した化合物のデータベースを、 表 1または表 2に示すフアルマコフォアをコンピュータ一ソフトウェアに供用する ことによりライブラリ一が得られる。 本発明のライブラリーを得る具体的な方法 は、 本発明の第七の態様に記載した通りである。 The database of compounds constructed from the fragment groups shown in Tables 3 and 4 The library 1 can be obtained by applying the pharmacophore shown in Table 1 or Table 2 to computer software. A specific method for obtaining the library of the present invention is as described in the seventh embodiment of the present invention.
コンピュータソフトウェアにより、 またはコンピュータソフトウエアに表 1ま たは表 2に示すフアルマコフォアを供用する手法、 例えば検索式、 の違いに より、 ライブラリーに含まれる候補化合物の数は多少上下する。 しかしこの違い は、 本質的な違いとなることはならない。  The number of candidate compounds contained in the library may vary slightly depending on the computer software or on the method of applying the pharmacophores shown in Table 1 or Table 2 to the computer software, such as the search formula. But this difference cannot be an essential difference.
本発明のライブラリ一をトリプターゼ活性を阻害する化合物のスクリ一ニング に用いることにより、 従来のランダムな化合物を含むライブラリ一若しくは デ一夕べ一スより、 トリプタ一ゼ阻害活性を有する化合物をかなり高い確率で得 ることができる。  By using the library of the present invention for screening compounds that inhibit tryptase activity, a compound having tryptase inhibitory activity can be considerably more probable than a library or a database containing conventional random compounds. Can be obtained at
本発明のライブラリ一は、 コンピュータソフトウェアにより得られた候補化合 物をすベて含まなくてもよい。 トリプタ一ゼ活性を阻害する化合物のスク リーニングをするためにある一定の方法で、 またはランダムに候補化合物の数を 減らしたライブラリ一も含まれる。 また、 別の候補化合物を含めて作成した ライブラリーも含まれる。 この場合、 含まれる別の候補化合物はライブラリ一中 半分以下であるライブラリーが好ましい。 より好ましくは、 1 74以下であり、 特に好ましくは 1ノ1 0以下である。 このようなライブラリ一は多様な観点から 必要な化合物をスクリーニングする場合に好適に対応できる利点がある。  The library of the present invention may not include all candidate compounds obtained by computer software. Libraries may also be included that screen for compounds that inhibit tryptase activity in a certain manner or randomly reduce the number of candidate compounds. It also includes libraries created with other candidate compounds. In this case, a library in which the other candidate compounds included are less than half of the library is preferred. It is more preferably at most 174, particularly preferably at most 10: 1. Such a library has an advantage that it can suitably cope with screening of necessary compounds from various viewpoints.
本発明の第十の態様は、 表 1または表 2に記載されるフアルマコフォアで ある。 該フアルマコフオアを得る方法は後述する実施例 6に記載した。 該フアル マコフォアを利用して本発明の第六の態様のスクリ一二ング方法または第七の態 様のドラッグデザィンを行うことが可能である。 また、 該フアルマコフォアを利 用して本発明の第八態様の化合物ァレイを作成することができる。 または本発明 の第九の態様のライブラリ一を得ることができる。 A tenth aspect of the present invention is a pharmacophore described in Table 1 or Table 2. The method for obtaining the pharmacophor is described in Example 6 below. The screening method according to the sixth aspect of the present invention or the seventh aspect utilizing the full-macophore. It is possible to perform various drag designs. Further, the compound array of the eighth aspect of the present invention can be prepared using the pharmacophore. Alternatively, the library of the ninth aspect of the present invention can be obtained.
また、 本発明は表 1または表 2に記載されるフアルマコフォアを記録、 記憶若 しくは格納した電子媒体、 またはプログラミングしたプログラムを提供する。 電 子媒体は、 メモリ一と呼ばれる電気的な媒体一次記憶媒体でも、 フロッピ一 ディスク、 ハードディスク、 光ディスク、 光磁気ディスク、 磁気テープなどの半 永久的な記憶媒体でも良い。 これらの電子媒体は、 コンピュータ読み取り可能な 電子媒体で有り、 例えば化合物スクリーニングに用いられるソフトウェア上に供 用することが可能である。 また、 化合物スクリーニングに用いられるソフトゥェ ァ等のプログラムに直接表 1または表 2に記載されるフアルマコフォアをプログ ラミングすることも可能であり、 また、 コンピュータ上に他のプログラムに独立 してプログラムを作成することも可能である。 これらのプログラムとして半永久 的に保持され、 単独で若しくは他のソフトウェアと提携させて、 化合物スクリー ニングを行うことが可能である。  Further, the present invention provides an electronic medium recording or storing or storing the pharmacophore described in Table 1 or Table 2, or a programmed program. The electronic medium may be a primary storage medium of an electrical medium called a memory or a semi-permanent storage medium such as a floppy disk, hard disk, optical disk, magneto-optical disk, or magnetic tape. These electronic media are computer-readable electronic media, and can be used, for example, on software used for compound screening. It is also possible to program the pharmacophore listed in Table 1 or Table 2 directly into a software or other program used for compound screening, and to create a program on a computer independently of other programs. It is also possible. These programs are held semi-permanently and can be used alone or in conjunction with other software for compound screening.
本発明の第十一の態様は、 表 1または表 2に記載されるフアルマコフォアを満 たすヒト /3トリプターゼ活性を阻害する下記のいずれかの化合物若しくはその薬 理学的に許容される塩である。  An eleventh aspect of the present invention is any one of the following compounds or pharmaceutically acceptable salts thereof that inhibits the human / 3 tryptase activity satisfying the pharmacophore described in Table 1 or Table 2. .
N— [ 1— [ 4一 （アミノメチル） フエニル] ピぺリジン一 4一ィル] 一 N— [ 1一 [ 4— (アミノメチル） フエニル] ピぺリジン一 4一ィルメチル] ァセト アミド、  N— [1 -— [4- (Aminomethyl) phenyl] piperidine-1-41] N— [1-1— [4- (Aminomethyl) phenyl] piperidine-1-41-methyl] acetamide
ビス [ 3— [ 4— (アミノメチル） フエニル] プロピル一 （2—アミノエチル ) ァミン、 Bis [3- [4- (aminomethyl) phenyl] propyl- (2-aminoethyl ) Amin,
N- [2- [N— [2- [4- (アミノメチル） フエノキシ] ェチル] ァミノ ] ェチル] 一 2—ナフタレンスルホンアミド、  N- [2- [N— [2- [4- (aminomethyl) phenoxy] ethyl] amino] ethyl] -1-naphthalenesulfonamide,
N- [2- [N— [3— [4- (アミノメチル） フエニル] プロパノィル] ― N—メチルァミノ] ェチル] 一 2—べンゾ [b] チォフェンカルポキサミド、 N- (4—ピペラジニルフエニル） 一 [1一 （4一フエニル） ベンゼンスルホ 二ルー 4ーピペリジン〗 カルボキサミド、  N- [2- [N— [3 -— [4- (Aminomethyl) phenyl] propanoyl] -N-methylamino] ethyl] -12-benzo [b] thiophencarpoxamide, N- (4-pipe Radinyl phenyl) 1 [1 1 (4 1 phenyl) benzenesulfo 2-ru 4-piperidine〗 carboxamide,
N— [1— （4一フエニル） ベンゼンスルホニル一 4—ピペリジル] 一 （4一 グァニジノベンゼン） カルポキサミド、  N— [1— (4-Phenyl) benzenesulfonyl-1-4-piperidyl] -1- (4-guanidinobenzene) carpoxamide,
N- [2— [N- [3— [4- (アミノメチル） フエニル] プロピル] —N— メチルァミノ] ェチル] —2, 3—ナフタレンジカルポキシミド、 若しくは  N- [2— [N- [3 -— [4- (aminomethyl) phenyl] propyl] —N—methylamino] ethyl] —2,3-naphthalenedicarboximide or
[1— [4- (アミノメチル） フエニル] ピぺリジン一 4一ィル] 一 [1— [ 4一 （アミノメチル） フエニル] ピぺリジン一 4一ィルメチル] ェチルァミン。 実施例  [1— [4- (Aminomethyl) phenyl] piperidine-41-yl] -1- [1 -— [4- (Aminomethyl) phenyl] piperidine-1-41-methyl] ethylamine. Example
以下に、 実施例をもって本発明を一層具体的に説明するが、 これらは一例とし て示すものであり、 本発明はこれらにより何等限定されるものではない。 また、 以下の記載において用いる略号は、 当該分野における慣用略号に基づくものであ る。  Hereinafter, the present invention will be described more specifically with reference to examples, but these are shown as examples, and the present invention is not limited thereto. Abbreviations used in the following description are based on common abbreviations in the relevant field.
実施例 1 トリプ夕一ゼの糖鎖切断 Example 1 Glycolytic cleavage of tryptic enzyme
ヒトリコンビナントトリプ夕ーゼ （P r ome ga社） （200 ^g/ml) 15 ml ( 3 mg) に Endo_N— ac e t y l g l u c o s ami n i d a s e (F 1 avob a c t e r i um s p. ) (生化学工業） 0. 485 Uを含む緩衝液 (l O OmM ME S H 5. 0, 8 mM EDTA, 0. 0 1 %アジ化 ナトリウム） を 15mlを加え、 5 Om 1遠心チューブに入れて 37 °Cで反応さ せた。 このチューブを 4本用意し、 計 12 Oml反応させた。 反応開始 24時間 後に氷冷下において反応を停止させ、 サンプルを U 1 t r a f r e e l 5 (M i 1 1 i p o r e) で 2. 5mlに濃縮した後、 FPLC s y s t em (Ph a r ma c i a) により精製を行なった。 カラムは Sup e r d e x 200HR26 Z60 (26mmx 60 Omm) を用い、 1M NaC 1 OmM ME S pH 6. 0をベット体積 （ 3 2 0 m 1 ) の 2倍量をカラムに流して平衡化 した。 ■ Human Recombinant Trypase (Promega) (200 ^ g / ml) Add 15 ml (3 mg) of Endo_N—acetylglucos amine (F 1 avob acteri um s p.) (Seikagaku Corporation) Add 15 ml of a buffer containing 0.485 U (lO OmM MESH 5.0, 8 mM EDTA, 0.01% sodium azide) and add 5 Om 1 The reaction was carried out at 37 ° C in a centrifuge tube. Four tubes were prepared, and a total of 12 Oml was reacted. 24 hours after the start of the reaction, the reaction was stopped under ice cooling, and the sample was concentrated to 2.5 ml with U1trafreel 5 (Mi11ipore), and then purified using FPLC system (Pharmacia). . The column used was Superdex 200HR26 Z60 (26 mm × 60 Omm), and 1 M NaC 1 OmM MES pH 6.0 was allowed to flow through the column at twice the bed volume (320 m 1) for equilibration. ■
トリプターゼ溶出画分を 3 7 m I回収し、 U l t r a f r e e l 5で 3 一 4ml程度に濃縮した。 その濃縮 H分へ 1. 7M NaC l、 1 OmM ME S pH6. 0を 10倍程度加え、 さらに遠心して濃縮した。 この操作を 3回繰 り返した。 これらの操作により、 遊離した糖鎖および原料由来のへパリンが部分 的に除去された、 濃縮された糖鎖切断トリプターゼの精製サンプルが 680 i l 得られた。 '  The tryptase-eluted fraction was collected at 37 ml and concentrated to about 34 ml with Ultrafele5. 1.7 M NaCl, 1 OmM MES pH 6.0 was added about 10 times to the concentrated H content, and the mixture was further centrifuged and concentrated. This operation was repeated three times. By these operations, 680 il of a purified purified sugar chain-cleaved tryptase from which the released sugar chains and the heparin derived from the raw material were partially removed was obtained. '
各精製サンプルのタンパク質濃度を紫外吸収法で測定したところ、 5. 5mg / 1であった。  When the protein concentration of each purified sample was measured by an ultraviolet absorption method, it was 5.5 mg / 1.
実施例 2 糖鎖切断したトリプ夕ーゼの電気泳動 Example 2 Electrophoresis of glycosylated trypsinase
実施例 1で得られた精製サンプル 10 に、 20 /1 の SDS s amp 1 e u f f e r (3. 2 % SDS, 0. 004% B r omo ph e n o 1 b 1 u e , 16% g l y c e r o l , 8 % 2— me r c a p t o e t h ano 1， 0. 1M Tr i s— HC 1 pH6. 8) を加えて、 100°Cで 5分加熱 し電気泳動サンプルを得た。 このサンプルに対して、 12% po l ya c r y 1 ami d e g e 1を用いた S D S— P AGEを行ない、 0. 2% Coom a s i e B r i l l i an t B 1 u eで泳動されたタンパクを染色した。 結 果を図 3に示す。 また比較として、 処理前トリプターゼも同様に電気泳動を行つ た。 SDS— PAGEによる分子量が約 33 k D aに単一バンドが認められた。 実施例 3 糖鎖切断したトリプ夕一ゼの活性測定 In the purified sample 10 obtained in Example 1, 20/1 SDS samp 1 euffer (3.2% SDS, 0.004% Bromoph eno 1b 1 ue, 16% glycerol, 8% 2— me rcaptoeth ano 1, 0.1 M Tris-HC1 pH 6.8) was added, and the mixture was heated at 100 ° C for 5 minutes to obtain an electrophoresis sample. The sample was subjected to SDS-PAGE using 12% poly cryacrylamide, and the electrophoresed protein was stained with 0.2% Coom asie Brilliant B 1 ue. The results are shown in Figure 3. As a comparison, electrophoresis was performed for pre-treatment tryptase in the same manner. A single band was observed at a molecular weight of about 33 kDa by SDS-PAGE. Example 3 Activity measurement of trypsinase with sugar chain cleavage
緩衝液 （l O OmM T r i s— HC 1 pH 7. 5, 200 n g/m l へパリン） 60 1中に、 100 ng/m 1に調製したリコンビナントトリ プターゼ若しくは糖鎖切断トリプタ一ゼを 20 し DMSOに 0. 01、 0. 03、 0. 1及び 0. 3 g/m 1の各濃度で溶解した B AB I M 1 I , 若しくは対照として DMSO 1 \ を加えた。 その後、 0. 5mMの 基質 （B o c - Ph e- S e r - Ar g- MCA) を 20 1 加え、 2 5 °C で 1時間反応させ、 20 %酢酸 100^ 1加えることにより反応を停止させた。 遊離した MCAを Ex= 355 nm， Em= 460 nmで蛍光強度を測定し、 こ の時の蛍光カウント値を a f t e rとした。 b e f o r eの値は、 BAB I Mま たは DM SO添加後に 100 1の 20%酢酸を加え、 その後基質を 20 1カロ えて 25 で 1時間反応させたものを蛍光測定して求めた。  Buffer solution (lO OmM Tris-HC1 pH 7.5, 200 ng / ml heparin) 60 1 Recombinant tryptase or sugar chain-cleaved tryptase adjusted to 100 ng / m1 was added to 20 BABIM1I dissolved at each concentration of 0.01, 0.03, 0.1 and 0.3 g / m1 or DMSO1 \ as a control was added to the mixture. Thereafter, add 20 1 of 0.5 mM substrate (Boc-Ph-Ser-Arg-MCA), react at 25 ° C for 1 hour, and stop the reaction by adding 100% 1 of 20% acetic acid. Was. The fluorescence intensity of the released MCA was measured at Ex = 355 nm and Em = 460 nm, and the fluorescence count value at this time was defined as after. The value of before was determined by adding BABIM or DMSO, adding 1001 of 20% acetic acid, then reacting the substrate at 201 calories and reacting at 25 for 1 hour, and measured the fluorescence.
酵素阻害反応は Δ== a f t e r-b e f o r eを指標とした。 酵素の活性は以 下の式で評価した。  The enzyme inhibition reaction was performed using Δ == after-before as an index. The activity of the enzyme was evaluated by the following formula.
酵素反応結果は after の値と beforeの値の差 （Δ) で表した。 The enzymatic reaction results were expressed as the difference (Δ) between the after value and the before value.
この時、 トリプターゼ活性を 1U = 「60分間に Δ蛍光カウントを 1, 000， 000上昇させるトリ プターゼ量」 At this time, tryptase activity 1U = “Amount of tryptase that increases Δ fluorescence count by 1,000,000 in 60 minutes”
と定義する。  Is defined.
また、 抑制率は以下の式で評価した。  The suppression rate was evaluated by the following equation.
抑制率 （％) = (A-B) / (A-C) X 100 (%)  Inhibition rate (%) = (A-B) / (A-C) X 100 (%)
A= (DMS 0のみを添加したサンプルの△蛍光カウント）  A = (△ fluorescence count of sample to which only DMS 0 was added)
B = (検体添加サンプル （c on t r o l) の△蛍光カウント）  B = (△ fluorescence count of sample added sample (con trol))
C = (酵素を含まないサンプル （b l ank) の△蛍光カウント） 結果を表 5および表 6に示す。 糖鎖切断したトリプ夕ーゼ活性は、 処理前 トリプ夕ーゼと比較して、 酵素活性はほぼ同じであり、 BAB IMの阻害活性も 両トリプタ一ゼに対してほぼ同等であった。  C = (△ fluorescence count of enzyme-free sample (blank)) The results are shown in Tables 5 and 6. The activity of the trypsinase from which the sugar chain was cleaved was almost the same as that of the trypsinase before the treatment, and the inhibitory activity of BABIM was almost the same for both tryptases.
表 5 糖鎮切断精製トリブターゼの酵素活性
Figure imgf000059_0001
表 6 B A B I Mの糖鎮切断精製トリプタ—ゼに対する阻害活性
Figure imgf000059_0002
実施例 4 Table 5 Enzyme activity of purified sugar-cleaved trybutase
Figure imgf000059_0001
Table 6 Inhibitory activity of BABIM on glycolytic cleavage purified tryptase
Figure imgf000059_0002
Example 4
〔糖鎖切断したトリプターゼと N— [2- [N— [3- [4一 （アミノメチル） フエニル] プロピル] ァミノ] ェチル] 一 2—ナフ夕レンスルホンアミド (化合 物 A， 実施例化合物 1) との複合体結晶の作成〕 [Sugar chain-cleaved tryptase and N- [2- [N- [3- [4-1 (aminomethyl) phenyl] propyl] amino] ethyl] -12-naphthylenesulfonamide (compound Preparation of Complex Crystal with Compound A and Example Compound 1)]
実施例 1で作成したトリプ夕一ゼを遠心限外濾過によって濃縮し、 次のような 組成の蛋白質溶液を調製した。 5. 5mgZmL糖鎖切断トリプ夕ーゼ、 1. 7 mo 1/L塩化ナトリウム、 10mmo l/L 3— （N—モルホリノ） プロパ ンスルホン酸 (pH6. 0) 。  The trypsinase prepared in Example 1 was concentrated by centrifugal ultrafiltration to prepare a protein solution having the following composition. 5. 5 mgZmL sugar chain-cleaved trypase, 1.7 mol / L sodium chloride, 10 mmol / L 3- (N-morpholino) propanesulfonic acid (pH 6.0).
トリプターゼと化合物 Aとの複合体は、 上記の蛋白質溶液 2 0 Lに 10mmo l/L 化合物 A、 1. 7mo 1 ZL塩化ナトリウム、 1 Ommo 1 ZL 3— （N—モルホリノ） プロパンスルホン酸 （ρΗ6· 0) 、 20 V ο 1 % 1, 4一ジォキサンを 20 L添加して調製した。  The complex of tryptase and compound A is obtained by adding 10 mmol / L compound A, 1.7 mol 1 ZL sodium chloride, 1 Ommo 1 ZL 3- (N-morpholino) propanesulfonic acid (ρΗ6 · 0), 20 Vο 1% 1,4-dioxane was added in an amount of 20 L.
結晶化用プレートは細胞培養用の 24穴プレート （リンブ口プレート） にマイ クロブリッジ ひ、ンプトンリサーチ社） を入れたものを使用した。 リザ一バー溶 液として 3 OwZv%ポリエチレングリコール 4000、 0. 2mo l/L酢酸 アンモニゥムおよび 0. lmo 1 ZL酢酸緩衝液 （pH 5. 0) を 800 Lを プレートのゥエルに入れた。 結晶化ド口ップはトリプターゼと化合物 Aの複合体 溶液、 リザーバー溶液および 3 Ow/v% 1， 5—ジァミノペンタンを 5対 4 対 1の比で混合して作成し、 マイクロブリッジ上に 2 を静置した。 このよう な結晶化ドロップを一度にプレート一枚分、 すなわち 24個作成した。 この状態 でゥエルのふちに真空グリースを塗り、 丸型カバ一グラスで密封した。 結晶化は 20°Cで行った。 結晶はセットアップした後、 数時間後には析出し始めた。 4日 後に、 析出した結晶のうち、 棒状の結晶として長さが 0. 5mm以下、 幅が 0. 075mm以上の結晶を、 放射光における回折実験に適当な大きさとして選 択した。 後述する回折実験には、 0. 075 x 0. 15 x 0. 5mm3 の大きさ の複合体結晶を用いた。 The crystallization plate used was a 24-well plate (limb plate) for cell culture with microbridge (Nampton Research). 800 L of 3 OwZv% polyethylene glycol 4000, 0.2 mol / L ammonium acetate and 0.1 mol LZ acetate buffer (pH 5.0) were placed in a plate well as a reservoir solution. The crystallization solution was prepared by mixing a complex solution of tryptase and compound A, a reservoir solution, and 3 Ow / v% 1,5-diaminopentane at a ratio of 5: 4: 1, and then put 2 on the microbridge. It was left still. Such crystallization drops were prepared for one plate at a time, that is, 24 crystallization drops were prepared. In this state, vacuum grease was applied to the edge of the well and sealed with a round cover glass. The crystallization was performed at 20 ° C. Crystals began to precipitate a few hours after setup. Four days later, of the precipitated crystals, rod-shaped crystals having a length of 0.5 mm or less and a width of 0.075 mm or more were selected as appropriate sizes for diffraction experiments using synchrotron radiation. The size of the later-described diffraction experiment, 0. 075 x 0. 15 x 0. 5mm 3 Was used.
X線回折実験は、 上記で作成し、 選択した複合体結晶を用いて大型放射光施設 X-ray diffraction experiments were conducted at a large synchrotron radiation facility using the complex crystals created above and selected.
SP r i ng— 8の兵庫県ビ一ムライン （BL 24XU) で行った。 データ収集 には R— AX I S Vイメージングプレート検出器 （R i gaku) を利用し、 振 動写真法によって振動角 1度で 180度の範囲を測定した。 測定の結果 2. 4人 分解能のデータセットを得た。 データの積分および強度の算出は MOSFLM ( A. Jones, . Bartels & P. Schwager (1977) in 'The Rotation Method in Cry stallography' , U. W. Arndt & A丄 Wonacoi t, eds, North Holland Publishing Co.) で実施し、 構造因子の算出は TRUNCATE (F r e n c h e t a 1. , Ac t a C r y s t . 21 (1978) , 517- 525) で行つた。 構 造解析は分子置換法によって進めた。 調査モデルとして、 1 AO Lを用いて、 X S I GHT (アクセルリス） によって適切な解を見出した。 モデル構築は XS I GHT (アクセルリス） によって SG Iワークステーション上で行い、 結晶学的 構造精密化は CNX (アクセルリス） で行った。 最終モデルは R因子 20. 3% (1 6 €因子は26. 0 %) r . m. s . 偏差が 0. 005976 (b o n d s) 、 1. 33334 (ang l e s) を有する。 後述する実施例 6のフアル マコフォアの構築に必要なヒト jSトリプターゼのアミノ酸残基、 その周辺のアミ ノ酸残基及び化合物 Aの最終モデルの座標を表 7に示す。 表 7は、 ヒト) 3トリプ 夕ーゼと化合物 Aの複合体の X線構造解析より得られた Research Col laboratory for Structural Bioinformatics (RCSB)PDB file format における座標である。 なお、 表 7の開示により、 後述する表 1のフアルマコフォアを抽出することがで さる。 また、 ヒト /3トリプターゼと化合物 Aの解析した結果のリポン図を図 4及び図 5に示す。 SP ri ng—8 was performed at Bumline, Hyogo (BL 24XU). The data was collected using a R-AX ISV imaging plate detector (Rigaku), and a range of 180 degrees was measured at a vibration angle of 1 degree by vibratory photography. Measurement results 2. A data set with a resolution of 4 people was obtained. Data integration and intensity calculations are provided by MOSFLM (A. Jones,. Bartels & P. Schwager (1977) in 'The Rotation Method in Cry stallography', UW Arndt & A 丄 Wonacoit, eds, North Holland Publishing Co.). The structure factor was calculated using TRUNCATE (Frencheta 1., Acta Cryst. 21 (1978), 517-525). Structural analysis was proceeded by the molecular replacement method. Using 1 AOL as a survey model, an appropriate solution was found by XSI GHT (Accelris). Model building was performed on the SGI workstation by XS I GHT (Accelris), and crystallographic structure refinement was performed by CNX (Accelris). The final model has an R factor of 20.3% (16 € factor is 26.0%) with r.m.s. deviations of 0.00005976 (bonds) and 1.33334 (angles). Table 7 shows the amino acid residues of human jS tryptase necessary for the construction of the pharmacophore of Example 6 described later, the amino acid residues around it, and the coordinates of the final model of compound A. Table 7 shows the coordinates in the PDB file format of the Research Col laboratory for Structural Bioinformatics (RCSB) obtained from the X-ray structural analysis of the complex of human) 3 trypase and compound A. By the disclosure in Table 7, it is possible to extract the pharmacophores in Table 1 described later. In addition, FIGS. 4 and 5 show Ripon diagrams of the results of analysis of human / 3 tryptase and compound A.
実施例 5 ソーキングによる複合体結晶化 Example 5 Complex Crystallization by Soaking
〔糖鎖切断したトリプ夕一ゼと N— [2— [N— [3— [4— （アミノメチル） フエニル] プロピル] 一 N—メチルァミノ] ェチル] 一 2—べンゾ [b] チオフ ェンカルポキサミド （化合物 B、 実施例化合物 2) との複合体化合物の作成〕 実施例 1で作成したトリプターゼを遠心限外濾過によって濃縮し、 次のような 組成の蛋白質溶液を調製した。 2. 75mgZmL糖鎖切断トリプターゼ、 1. 7 mo 1 ZL塩化ナトリウム、 l Ommo lZL 3— （N—モルホリノ) プロパンスルホン酸 （pH6. 0) 。  [Glycanase-cleaved trypticase and N— [2-—N— [3-—4- (aminomethyl) phenyl] propyl] -1-N-methylamino] ethyl] -12-benzo [b] thiophene Preparation of Complex Compound with Ncarpoxamide (Compound B, Example Compound 2)] The tryptase prepared in Example 1 was concentrated by centrifugal ultrafiltration to prepare a protein solution having the following composition. 2. 75 mg ZmL sugar chain-cleaving tryptase, 1.7 mo 1 ZL sodium chloride, l Ommo lZL 3-(N-morpholino) propanesulfonic acid (pH 6.0).
この結晶化用蛋白質溶液を用いて、 実施例 4に準じて結晶化を行った。 放射光における回折実験に適当な大きさとして選択したトリプターゼのみの結晶 を、 8. 75mmo 1 /Lの化合物 Bを溶解させた 3 Ow/v%ポリエチ レングリコール 4000、 0. 2mo 1 ZL酢酸アンモニゥム、 1. Omo lZ L NaC 0. 1 m o 1 /L酢酸緩衝液 p H 5. 0の溶液に浸漬させること で、 ソーキングによる複合体結晶化を行った。 浸漬は 20°Cで、 24時間行い、 複合体結晶を得た。 後述する回折実験には、 0. 1x0. 1x0. 3mm3 の大 きさの複合体結晶を用いた。 Using this protein solution for crystallization, crystallization was carried out according to Example 4. A crystal of tryptase alone selected as a suitable size for the diffraction experiment in synchrotron radiation was obtained by dissolving 8.75 mmol / L of compound B in 3 Ow / v% polyethylene glycol 4000, 0.2 mol 1 ZL ammonium acetate, 1. The complex was crystallized by soaking by immersion in a solution of OmolZL NaC 0.1 mo1 / L acetate buffer pH 5.0. Immersion was performed at 20 ° C for 24 hours to obtain composite crystals. In a later-described diffraction experiment, a composite crystal having a size of 0.1 × 0.1 × 1 × 0.3 mm 3 was used.
X線回折実験は、 実施例 4に記載した方法と同様に行い、 測定の結果 2. 0A 分解能のデータセットを得た。 データの解析についても実施例 4に記載した方法 と同様に行った。 最終モデルは R因子 21. 3% (R f r e e因子は 24. 1 % ) r . m. s . 偏差が 0 · 005769 (bonds) 、 1. 36917 (an g 1 e s ) を有する。 後述する実施例 6のフアルマコフォアの構築に必要なヒト βトリプターゼのアミノ酸残基、 その周辺のアミノ酸残基及び化合物 Βの最終モ デルの座標を表 8に示す。 表 8は、 ヒト) 3トリプ夕一ゼと化合物 Βの複合体の X 線構造解析より得られた RCSB PDB f i le f ormatにおける座標である。 なお、 表 8 の開示により、 後述する表 2のフアルマコフォアを抽出することができる。 また、 ヒト /3トリプターゼと化合物 Bの解析した結果のリポン図を図 6及び図 7に示す。 The X-ray diffraction experiment was performed in the same manner as described in Example 4, and as a result of the measurement, a data set having a resolution of 2.0 A was obtained. Data analysis was performed in the same manner as described in Example 4. The final model has an R factor of 21.3% (R free factor is 24.1%) r.m.s.deviation of 0 · 005769 (bonds), 1.36917 (an g 1 es). Table 8 shows the amino acid residues of human β-tryptase necessary for construction of the pharmacophore of Example 6 described later, the surrounding amino acid residues, and the coordinates of the final model of compound II. Table 8 shows the coordinates in the RCSB PDB file format obtained by X-ray structural analysis of the complex of human (3) trypase and compound Β. By the disclosure in Table 8, the pharmacophores in Table 2 described later can be extracted. 6 and 7 show the Ripon diagrams of the results of analysis of human / 3 tryptase and compound B.
このようにあらかじめトリプ夕一ゼのみの結晶を作成しておけば、 ソ一キング 法を用いることで僅か 1日でトリプターゼと化合物の複合体結晶を得ることがで きる。 また放射光を用いれば、 1結晶あたりの測定時間は 3時間程度で終 了する。 また続く解析は分子置換法を用いているため 2時間程度でよく、 最短で ソーキングを開始してから 2日あればソーキングに用いたトリプ夕一ゼ活性を阻 害する化合物の候補化合物が卜リプターゼ分子と結合するか否かを判断すること ができる。  Thus, if crystals of only trypsinase are prepared in advance, a complex crystal of tryptase and a compound can be obtained in only one day by using the soaking method. If synchrotron radiation is used, the measurement time per crystal is about 3 hours. The subsequent analysis uses the molecular replacement method, so it takes about 2 hours. In the shortest two days after starting soaking, the candidate compound that inhibits trypticase activity used for soaking is a tryptase molecule. It can be determined whether or not to combine.
従って、 糖鎖切断したトリプ夕ーゼの結晶を用いて、 ソ一キング法を行うこと により通常よりもかなりの短時間で複合体結晶を調製することが可能でありこれ を解析することで、 トリプターゼ活性を阻害する化合物の候補化合物の卜リ プターゼとの結合を確認することができる。 つまりソーキング法を利用すること で結合サイトの確認まで含めた卜リプターゼ活性を阻害する化合物のスクリ一二 ングが可能であることが判明した。  Therefore, it is possible to prepare a complex crystal in a considerably shorter time than usual by performing the soaking method using the crystal of the trypsinase with the sugar chain cleaved. It is possible to confirm the binding of a candidate compound that inhibits tryptase activity to tryptase. In other words, it was found that screening of compounds that inhibit tryptase activity, including confirmation of the binding site, was possible by using the soaking method.
実施例 6 フアルマコフォアの構築 Example 6 Construction of a Pharmacophore
(1 ) 化合物 Aとヒト 3トリプタ一ゼの共結晶構造から構築した 実施例 4で得た化合物 Aとヒト ]3トリプターゼの共結晶構造の座標を分子設計 ソフトウェア Insight I Iに供用して、 化合物 A分子から 6 A以内に存在する ト リブ夕一ゼのアミノ酸残基を抽出した。 抽出した結果を表 9に示す。 (1) Constructed from the co-crystal structure of compound A and human 3-tryptase The coordinates of the co-crystal structure of compound A and human] 3 tryptase obtained in Example 4 were applied to the molecular design software Insight II to determine the amino acid residues of tributylase present within 6 A from the compound A molecule. Extracted. Table 9 shows the extracted results.
表 9  Table 9
Figure imgf000064_0001
Figure imgf000064_0001
次に、 抽出したアミノ酸残基と、 化合物 A分子との相互作用を解析した。 解析 した結果を化合物 Aと相互作用を示すヒト /3トリプターゼのアミノ酸残基の立体 図として図 8に、 ヒト i3トリプ夕一ゼのアミノ酸残基と化合物 Aとの立体図とし て図 9に示す。  Next, the interaction between the extracted amino acid residues and the compound A molecule was analyzed. The results of the analysis are shown in Fig. 8 as a three-dimensional diagram of the amino acid residues of human / 3 tryptase interacting with compound A, and in Fig. 9 as a three-dimensional diagram of the amino acid residues of human i3 trypticase and compound A. .
解析した結果、 化合物 Aのベンジルァミンは、 S1ポケットの Aspl 89とイオン結 合を有しており、 アミノメチル基を有するベンゼン環は、 S1ポケットの疎水的な 環境において、 疎水的な相互作用を有していた。 この領域は、 i3トリプ夕一ゼを 阻害する強さを調整する部分であり、 エラス夕一ゼなど、 S1ポケットの底の形状 が疎水的なセリンプロテアーゼに対しては、 選択性を発揮し得るが、 型のセリンプロテアーゼに対しては十分な選択性を発揮する相互作用というより も、 むしろ、 ]3トリプターゼを強く阻害する上で重要な相互作用と位置付けるこ とができた。 As a result of the analysis, it was found that benzylamine of compound A has an ionic bond with Aspl 89 in the S1 pocket, and the benzene ring having an aminomethyl group has a hydrophobic interaction in the hydrophobic environment of the S1 pocket. Was. This region regulates the strength of inhibition of i3 trypsinase, and can exhibit selectivity for serine proteases with a hydrophobic S1 pocket bottom, such as elasinase. But, Rather than interacting with sufficient selectivity for the type of serine protease, it could be positioned as an important interaction in strongly inhibiting] 3 tryptase.
フアルマコフォアのこの部位に関する条件は、 Aspl89とベンジルァミンの N原 子との距離で水素結合可能な領域で規定した。 すなわち、 Aspl89側鎖の酸素原子 を中心として 3.21 ±0.5 人以内に窒素原子が位置することで規定.した。  The conditions for this site in the pharmacophore were defined as the region where hydrogen bonding is possible at the distance between Aspl89 and the N atom of benzylamine. That is, it was defined that the nitrogen atom was located within 3.21 ± 0.5 people around the oxygen atom in the side chain of Aspl89.
フアルマコフォアの、 S1ポケッ 卜における疎水的環境をあらわす条件 は、 Glnl92, Trp215, Gly219の C αからの距離がそれぞれ 5.2 ±1.4人、 3.9 土 1.4人、 6.1 ±1.4人で形成される空間に疎水性官能基の重心が位置することで規 定した。 好ましくは、 疎水性官能基が芳香環もしくは環状炭化水素であり、 また、 疎水性官能基の重心がトリプターゼと立体障害をおこさずに存在すること であった。 化合物 Αのスルホンアミドは、 ヒト )3トリプタ一ゼに特異的な 90番 ループとの相互作用を形成し、 ヒト i3トリプ夕ーゼに対する選択性を発揮する上 で重要な部位であった。 直接的な相互作用は、 Ala97 の主鎖と水素結合、 及び、 Gln98 の側鎖との水素結合であった。 フアルマコフォアのこの部位に関する条件 は、 Ala97主鎖の窒素原子より 2.9±0.5人以内、 あるいは Gln98 の N ε原子より 3.2±0.5人以内に水素結合受容基 （Hydrogen- bond Acceptor) が位置することで 規定した。 - 水素結合受容基は、 好ましくは、 酸素、 窒素、 硫黄等のへテロ原子、 またはフッ素等の電気陰性度が大きい基であった。 具体的にはカルボニル酸素、 エーテル酸素、 アルコール酸素、 ィミン窒素等であった。  The conditions that express the hydrophobic environment in the S1 pocket of the pharmacophore are as follows. It was defined by the position of the center of gravity of the functional group. Preferably, the hydrophobic functional group is an aromatic ring or a cyclic hydrocarbon, and the center of gravity of the hydrophobic functional group is present without causing steric hindrance to tryptase. The sulfonamide of compound (2) forms an interaction with the 90th loop specific to human) 3 tryptase, and is an important site for exerting selectivity for human i3 trypase. Direct interactions were hydrogen bonding with the main chain of Ala97 and hydrogen bonding with the side chain of Gln98. The conditions for this site in the pharmacophore are defined by the presence of a hydrogen-bond acceptor within 2.9 ± 0.5 of the nitrogen atom of the Ala97 main chain or within 3.2 ± 0.5 of the Nε atom of Gln98. did. The hydrogen bond accepting group was preferably a heteroatom such as oxygen, nitrogen or sulfur, or a group having a high electronegativity such as fluorine. Specifically, they were carbonyl oxygen, ether oxygen, alcohol oxygen, imine nitrogen and the like.
また、 ヒト /3トリプタ一ゼは 4量体を形成するため、 化合物 Aは隣接する卜リ プ夕一ゼと相互作用していた。 このため、 化合物 Aは、 ヒト i3トリプターゼを選 択的に阻害し得ることがわかった。 Since human / 3 tryptase forms a tetramer, compound A is He interacted with Puyuichi. For this reason, it was found that compound A can selectively inhibit human i3 tryptase.
フアルマコフォアのこの部位に関する条件は、 Tyr95， Thr96および隣接するト リブ夕ーゼの Glu217の C からの距離がそれぞれ 6.9±1.4人、 5.1±1.4人、 7.7Conditions for this site Fuarumakofoa is, Tyr95, Thr96 and distances 6.9 ± 1.4 people each from C of Glu217 adjacent preparative ribs evening over Ze, 5.1 ± 1.4 people, 7.7
±1.4 Aで形成される空間に芳香環もしくは環状炭化水素の重心がトリプターゼ と立体障害を起こさずに存在することで規定した。 芳香環もしくは環状炭化水素 の大きさは好ましくは、 ベンゼン環 1個の大きさからベンゼン環 3個が縮環した 大きさであった。 より好ましくはベンゼン環 2個が縮環した大きさであった。 以上、 ヒト 3トリプターゼと化合物 A複合体結晶構造解析から特定された相互 作用解析に有用なヒト /3トリプタ一ゼのアミノ酸残基、 化合物の規定、 相互作用 様式、 及びフアルマコフォアの各部位に関する条件のまとめを表 1に示す。 また フアルマコフォアの模式図を図 10に示す。 It is defined that the center of gravity of the aromatic ring or cyclic hydrocarbon exists in the space formed by ± 1.4 A without causing steric hindrance to tryptase. The size of the aromatic ring or cyclic hydrocarbon was preferably a size obtained by condensing three benzene rings from one benzene ring. More preferably, the size was such that two benzene rings were condensed. The amino acid residues of human / 3 tryptase useful for the interaction analysis identified from the crystal structure analysis of human 3 tryptase and compound A complex, the definition of the compound, the interaction mode, and the conditions for each site of the pharmacophore The summary is shown in Table 1. Fig. 10 shows a schematic diagram of the pharmacophore.
Figure imgf000066_0001
6 6 日本国特許庁 25.08.03 これら、 フアルマコフォアの 4箇所の条件を満たす卜リブ夕ーゼ活性を阻害す る化合物をコンピュータスクリーニングすることで、 ヒト )3トリプ夕ーゼのトリ プ夕一ゼ活性を阻害する化合物のスクリーニングが可能となり、 このフアルマコ . フォアを利用した分子設計によって、 より、 強力で選択的なヒト ιδトリプ夕ーゼ 活性を阻害する化合物のデザィンが可能となった。
Figure imgf000066_0001
6 6 Japan Patent Office 25.08.03 Computer screening of compounds that inhibit the tribase activity that satisfies the four conditions of the pharmacophore was carried out by computer screening. It has become possible to screen for compounds that inhibit the activity, and this molecular design using the pharmacophore has made it possible to design more potent and selective compounds that inhibit human ιδ-tripsease activity.
(2) 化合物 Βとヒト øトリプ夕一ゼの共結晶構造から構築したフアルマコフォア  (2) Pharmacophore constructed from the co-crystal structure of compound Β and human ø-trippase
実施例 5で得た化合物 Βとヒ卜 |3トリプ夕一ゼの共結晶構造の座標を分子設計 ソフトウェア Ins ight I Iに供用して、 化合物 B分子から 6 A以内に存在する 3ト リプタ一ゼのアミノ酸残基を抽出した。 抽出した結果を表 1 0に示す。  The coordinates of the co-crystal structure of the compound Β and the human | 3 trypase obtained in Example 5 were applied to the molecular design software Insight II, and the 3 transcriptase existing within 6 A from the compound B molecule was used. Amino acid residues were extracted. Table 10 shows the results of the extraction.
表 10Table 10
Figure imgf000067_0001
Figure imgf000067_0001
注 1 ： 4量体を形成するトリプターゼにおいて、 隣接するトリプターゼの G I U217  Note 1: In tryptase forming tetramer, G I U217 of adjacent tryptase
次に、 抽出したアミノ酸残基と、 化合物 Β分子との相互作用を解析した。 解析 しだ結果を化合物 Βと相互作用を示すヒト /3トリプターゼのアミノ酸残基の立体 差替え用紙 （規則 26) 図として図 1 1に、 ヒト トリプターゼのアミノ酸残基と化合物 Bとの 体図と して図 1 2に示す。 Next, the interaction between the extracted amino acid residue and the compound II molecule was analyzed. Analyze the analysis results. Replacement paper for amino acid residues of human / 3 tryptase that interacts with compound 用紙 (Rule 26) FIG. 11 is a diagram, and FIG. 12 is a diagram of the amino acid residues of human tryptase and compound B.
解析した結果、 化合物 Bのベンジルァミン部位も、 化合物 Aと同様に S1ポケッ トの Aspl 89とイオン結合を有しており、 ベンジルァミンのついたベンゼン環は、 S1ポケットの疎水的な環境において疎水的な相互作用を有していることが判明し た。 前述したように、 この領域は、 jSトリプターゼを阻害する強さを調整する部 分であり、 エラス夕ーゼなど、 S1ポケットの底の形状が疎水的なセリンプロ テア一ゼに対しては、 選択性を発揮し得るが、 トリプシン型のセリンプロテア一 ゼに対しては十分な選択性を発揮する相互作用というよりも、 むしろ、 3トリプ ターゼを強く阻害する上で重要な相互作用と位置付けることができた。  As a result of the analysis, the benzylamine site of compound B also has an ionic bond with Aspl 89 of the S1 pocket, similar to compound A, and the benzene ring with benzylamine is hydrophobic in the hydrophobic environment of the S1 pocket. It was found to have an interaction. As described above, this region is a part that regulates the strength of inhibiting jS tryptase, and is a selective component for serine proteases with a hydrophobic S1 pocket bottom, such as elasase. However, rather than interacting with sufficient selectivity for trypsin-type serine protease, it may be regarded as an important interaction for strongly inhibiting 3 tryptase. did it.
フアルマコフォアのこの部位に関する条件は、 Aspl 89とベンジルァミンの N原 子との距離で水素結合可能な領域で規定した。 すなわち、 Aspl 89側鎖の酸素原子 を中心として 3. 21 ± 0. 5 A以内に窒素原子が位置することで規定した。  The conditions for this site in the pharmacophore were defined as a region capable of hydrogen bonding at the distance between Aspl 89 and the N atom of benzylamine. That is, it was defined that the nitrogen atom was located within 3.21 ± 0.5 A centering on the oxygen atom of the side chain of Aspl 89.
フアルマコフォアの、 S1ポケットにおける疎水的環境をあらわす条件は、 Glnl 92, Trp215, Gly219の C ひからの距離がそれぞれ 5. 2 ± 1 . 4人、 3. 9 ± 1. 4人、 6. 1 ± 1. 4人で形成される空間に疎水性官能基の重心が位置することで規定した。 好ましくは、 疎水性官能基が芳香環もしくは環状炭化水素であり、 また、 疎水 性官能基の重心が卜リプターゼと立体障害をおこさずに存在することであつた。 化合物 Bのアミドは、 トリプターゼに特異的な 9 0番ループとの相互作用を形 成し、 ヒト ]3トリプターゼに対する選択性を発揮する上で重要な部位であった。 直接的な相互作用は、 Gln98 の側鎖との水素結合であった。  The conditions that express the hydrophobic environment in the S1 pocket of the pharmacophore are as follows: Glnl 92, Trp215, and Gly219 are at distances of 5.2 ± 1.4, 3.9 ± 1.4, and 6.1 ±, respectively, from C. 1. It was defined that the center of gravity of the hydrophobic functional group was located in the space formed by four people. Preferably, the hydrophobic functional group is an aromatic ring or a cyclic hydrocarbon, and the center of gravity of the hydrophobic functional group is present without causing steric hindrance to tryptase. The amide of compound B formed an interaction with the tryptase-specific loop 90, and was an important site for exerting selectivity for human] 3 tryptase. The direct interaction was a hydrogen bond with the side chain of Gln98.
：の部位に関する条件は、 Gln98 の N ε原子より 3. 3 ± 0. 5 入以内に水素結合受容基 (Hydrogen— bond Acceptor) が位置することで規定し た。 水素結合受容基は、 好ましくは、 酸素、 窒素、 硫黄等のへテロ原子、 または フッ素等の電気陰性度が大きい基であった。 具体的にはカルポニル酸素、 ェ一テ ル酸素、 アルコール酸素、 ィミン窒素等であった。 : The condition for the site is 3.3 ± 0.5 from the N ε atom of Gln98. It was specified that a hydrogen bond acceptor (Hydrogen-bond Acceptor) was located within the region. The hydrogen bond accepting group was preferably a heteroatom such as oxygen, nitrogen or sulfur, or a group having a high electronegativity such as fluorine. Specifically, it was carbonyl oxygen, ether oxygen, alcohol oxygen, imine nitrogen and the like.
また、 アミドに結合した芳香環は、 隣接する分子と直接的に相互作用すること によって、 極めて特徴的な形で、 トリプターゼ阻害活性を発揮していた。 この結 合様式は、 4量体を形成する卜リプターゼにおいてのみ形成される結合様式であ るため、 i3トリプタ一ゼ活性を選択的に阻害する化合物を探索もしくは、 設計す る上で重要な情報であった。  In addition, the aromatic ring bound to the amide exerted a tryptase inhibitory activity in a very characteristic manner by directly interacting with an adjacent molecule. Since this binding mode is a binding mode formed only by tetrapterase tryptase, it is important information for searching or designing compounds that selectively inhibit i3 tryptase activity. Met.
フアルマコフォアのこの部位に関する条件は、 （A) アミド結合を形成する 窒素、 水素、 炭素及び酸素の 4原子を含むアミド結合及び芳香環がほぼ同一平面 に存在し、 （B) 該平面が、 もう一つの同一化合物中の該平面と、 3. 5 ± 0. 2A以内 に平行な位置関係を形成し、 π— π相互作用をしていることで規定した。  The conditions for this site in the pharmacophore are: (A) the amide bond forming the amide bond, the amide bond containing four atoms of nitrogen, hydrogen, carbon and oxygen and the aromatic ring are almost in the same plane; A parallel positional relationship was formed within 3.5 ± 0.2 A with the planes in two identical compounds, and it was defined as having a π-π interaction.
また、 好ましくは、 フアルマコフォアを満たす分子は、 もう一つの同一化合物 の分子と、 C 2回転軸を中心に 1 8 0 °C回転した位置関係に存在することであつ た。  Preferably, the molecule that satisfies the pharmacophore has a positional relationship of 180 ° C. rotation about the C 2 rotation axis with another molecule of the same compound.
以上、 ヒト )3トリプターゼと化合物 B複合体結晶構造解析から特定された相互 作用解析に有用なアミノ酸残基のまとめを表 2に示す。 またフアルマコフォアの 模式図を図 1 3に示す。  Table 2 summarizes the amino acid residues useful for the interaction analysis identified from the crystal structure analysis of the complex of human) 3 tryptase and compound B. Figure 13 shows a schematic diagram of the pharmacophore.
これら、 フアルマコフォアの 4箇所の条件を満たすトリプタ一ゼ活性を阻害す る化合物をコンピュータスクリーニングすることで、 ヒト /3トリプターゼ活性を 阻害する化合物を、 スクリーニングが可能となるし、 このフアルマコフォアを利 用した分子設計によって、 より、 強力で選択的なヒト 3トリプタ一ゼ活性を阻害 する化合物のデザィンが可能となった。 表 2 Computer screening of compounds that inhibit tryptase activity that satisfies the four conditions of the pharmacophore enables screening of compounds that inhibit human / 3 tryptase activity. The molecular design used has allowed for more powerful and selective design of compounds that inhibit human 3-tryptase activity. Table 2
Figure imgf000070_0001
実施例 7 フオルマコフォアの i n s i l i c o供与
Figure imgf000070_0001
Example 7 In silico donation of formacophore
(1 ) 蛋白構造に発生させたフアルマコフォアを利用したバーチャルスクリー ニング  (1) Virtual screening using pharmacophores generated in protein structures
実施例 6で得た表 1のフアルマコフォアまたは表 2のフアルマコフォアを解析 用ソフトウエアとして DOCKを使用してヒト /3トリプ夕ーゼに結合可能な化合物の コンピュータスクリーニングを行った。  The pharmacophore of Table 1 or the pharmacophore of Table 2 obtained in Example 6 was subjected to computer screening for a compound capable of binding to human / 3 trypsinase using DOCK as analysis software.
まず、 SPHGENプログラムを用いて、 トリプタ一ゼ活性を阻害する化合物が結合 し得ると考えられるポケット及びクレーブの周囲に対してスフエアと呼ばれる仮 想の球体を配置した。 具体的には、 トリプターゼと、 化合物 Aあるいは、 化合 物 Bの原子から 7人の距離にあるァミノ酸残基の周辺にスフエアを配した。 次に、 GRIDプログラムを用いてフアルマコフォアを発生させた ]3トリプタ一ゼ 分子の領域に対してグリッド （格子） を発生させ、 指定された範囲の受容体残基 における電子的及び立体的な環境を、 各ダリッド上のスカラー値として表現 した。 First, using the SPHGEN program, virtual spheres called spheres were placed around pockets and claves where compounds that inhibit tryptase activity could bind. Specifically, tryptase and compound A or compound A space was placed around the amino acid residue, which was 7 people away from the B atom. Next, a pharmacophore was generated using the GRID program.] A grid was generated for the region of the 3-tryptase molecule, and the electronic and steric environment of the specified range of receptor residues was determined. , Expressed as a scalar value on each dalid.
化合物デ一夕べ一スの検索には、 DOCKプログラムを用いて、 あらかじめ準備し すこ βトリプターゼ活性を阻害する化合物の探索用のバーチャルデータベース等を 対象としてスクリーニングに供した。  Compounds were searched overnight using the DOCK program, which was screened using a virtual database for searching for compounds that inhibit β-tryptase activity.
ポケット及びクレーブの周囲に存在するスフエアの近傍に位置し、 かつ、 グリッド上の立体的要素、 あるいは電子的要素と反発しないような 3次元配座を 取るような化合物を探索した。 この際、 ドッキングされた化合物の 3次元配 座は、 DOCKプログラムに内蔵された配座発生機能により最適化し、 ヒット化合物 を選択した。 ヒットした化合物のうち、 後述する実施例化合物 5を表 1に合致す る化合物の例として、 後述する実施例化合物 1 2を表 2に合致する化合物の例と して、 それぞれ後述する実施例を行った。  We searched for a compound that was located near the space around the pocket and clave, and that had a three-dimensional conformation that did not repel the three-dimensional or electronic elements on the grid. At this time, the three-dimensional conformation of the docked compound was optimized by the conformation generation function built in the DOCK program, and a hit compound was selected. Among the hit compounds, Example Compound 5 described later is defined as an example of a compound matching Table 1, and Example Compound 12 described below is defined as an example of a compound matching Table 2, and Examples described later are respectively described. went.
( 2 ) 活性コンフオメーションから既定されるフアルマコフォアを利用したバー チャルスクリ一ニング  (2) Virtual screening using pharmacophore defined from active conformation
( 2 ) - 1  ( twenty one
解析用ソフトウェアとして Catalys t (アクセルリス社） を用いた。 表 7に記載 の複合体の結晶座標から、 化合物 Aの座標のみを Ins ight I I (アクセルリス社） を用いて抽出し、 Cat a l ys tに入力した。 次に実施例 6で得た表 1のフアル マコフォアを用い、 それぞれ下記のような空間に特性球を配置した。 特性球とし JP2003/009738 Catalyst (Accelris) was used as analysis software. From the crystal coordinates of the complex shown in Table 7, only the coordinates of compound A were extracted using Insight II (Accelris) and input to Catalyst. Next, using the pharmacophores of Table 1 obtained in Example 6, characteristic spheres were arranged in the following spaces, respectively. As a characteristic sphere JP2003 / 009738
71  71
ては① Positive Ionizable 、 ©Hydrophobic 、 ③ Hydrogen— bond Acceptor、 ④ Ring Aromaticの 4種類を用いた。 Four types were used: (1) Positive Ionizable, © Hydrophobic, (3) Hydrogen-bond Acceptor, and (4) Ring Aromatic.
①化合物 Aのアミノメチル基窒素原子を中心として半径 1. 5 Aの球を置 き、 Positive Ionizable に相当する特性球とした。  (1) A sphere with a radius of 1.5 A centered on the nitrogen atom of the aminomethyl group of compound A was used as a characteristic sphere equivalent to Positive Ionizable.
②ァミノメチルフエニル基のフエニル基の重心を中心として半径 1. 5人の球を 置き、 Hydrophobic に相当する特性球とした。 (2) A ball with a radius of 1.5 was placed around the center of gravity of the phenyl group of the aminomethylphenyl group, and a characteristic sphere equivalent to Hydrophobic was used.
③スルホンアミドの酸素原子を中心として半径 1. 5人の球を置いた。 また、 ス ルホンアミ ド酸素原子より酸素原子の非共有電子対の向きに直線を引き、 スルホンアミド酸素原子より 3人離れた位置を中心として半径 1. 5入の球を置 いた。 これら 2つの球を Hydrogen— bond Acceptorに相当する特性球とした。 (3) A radius of 1.5 was placed around the oxygen atom of the sulfonamide. In addition, a straight line was drawn in the direction of the lone pair of the oxygen atom from the sulfonamide oxygen atom, and a sphere with a radius of 1.5 was placed around the position three people away from the sulfonamide oxygen atom. These two spheres were used as characteristic spheres corresponding to the Hydrogen-bond Acceptor.
④ナフタレン環のスルホンアミド側ベンゼン環の重心を中心として半径 1. 5 A の球を置いた。 また、 この重心から芳香環平面に対して垂直な向きに直線を 弓 Iき、 化合物 Aから見て ]3トリプターゼ側であり、 かつ上記の重心より 3 A離れ た点を中心として 2つ目の半径 1. 5人の球を置いた。 これら 2つの球を Ring Aromaticに相当する特性球とした。 球 A 1.5 A radius sphere was placed around the center of gravity of the benzene ring on the sulfonamide side of the naphthalene ring. Also, a straight line is drawn from this center of gravity in a direction perpendicular to the plane of the aromatic ring. Radius 1. Place 5 balls. These two spheres are characteristic spheres equivalent to Ring Aromatic.
特性球の図を図 14に示す。  Figure 14 shows the characteristic sphere.
(2) 一 2  (2) One 2
また、 表 8に記載の複合体の結晶座標から、 化合物 Bの座標のみを Insight II を用いて抽出し、 Catalystに入力した。 次に実施例 6で得た表 2のフアルマ コフォアを用い、 空間に特性球を配置した。  From the crystal coordinates of the complex shown in Table 8, only the coordinates of Compound B were extracted using Insight II and input to Catalyst. Next, using the pharmacophore of Table 2 obtained in Example 6, characteristic spheres were arranged in space.
特性球として① Positive Ionizable 、 ©Hydrophobic 、 ③ Hydrogen— bond Acceptor, ④ Ring Aromaticの 4種類を用い、 それぞれ下記のような空間に配置 TJP2003/009738 Four types of characteristic spheres, (1) Positive Ionizable, © Hydrophobic, (3) Hydrogen—bond Acceptor, and (4) Ring Aromatic, are placed in the following spaces, respectively. TJP2003 / 009738
72  72
した。 did.
①化合物 Bのァミノメチル基の窒素原子を中心として半径 1. 5人の球を置き、 正電荷 Positive Ionizable に相当する特性球とした。  (1) A sphere with a radius of 1.5 centered on the nitrogen atom of the aminomethyl group of Compound B was used as a characteristic sphere equivalent to Positive Ionizable.
②アミノメチルフエニル基のフエニル基の重心を中心として半径 1. 5人の球を 置き、 Hydrophobic に相当する特性球とした。  (2) A ball with a radius of 1.5 was placed around the center of gravity of the phenyl group of the aminomethylphenyl group, and a characteristic sphere equivalent to Hydrophobic was placed.
③アミド結合の酸素原子を中心として半径 1. 5人の球を置いた。 また、 スルホンアミド酸素原子より酸素原子の非共有電子対の向きに直線を引き、 スルホンアミド酸素原子より 3人離れた位置を中心として半径 1. 5人の球を置 いた。 これた 2つの球を Hydrogen— bond Acceptor に相当する特性球とした。 ④ベンゾチォフェンのチォフェン環の重心を中心として半径 1. 5人の球を置い た。 また、 この重心から芳香環平面に対して垂直な向きに直線を引き、 化合物 B から見て /3トリプ夕一ゼ側であり、 かつ上記の重心より 3 A離れた点を中心とし て 2つ目の半径 1. 5人の球を置いた。 これら 2つの球を Ring Aromaticに相当 する特性球とした。  (3) A sphere with a radius of 1.5 was placed around the oxygen atom of the amide bond. In addition, a straight line was drawn in the direction of the lone pair of the oxygen atom from the sulfonamide oxygen atom, and a sphere with a radius of 1.5 was placed around the position three people away from the sulfonamide oxygen atom. These two spheres were used as characteristic spheres equivalent to the Hydrogen-bond Acceptor.球 A ball with a radius of 1.5 was placed around the center of gravity of the thiophene ring of benzothiophene. A straight line was drawn from this center of gravity in a direction perpendicular to the plane of the aromatic ring. Eye radius 1. Placed five spheres. These two spheres are characteristic spheres equivalent to Ring Aromatic.
特性球の図を図 15に示す。  Figure 15 shows the characteristic sphere.
(2) 一 3  (2) One three
また、 （2) — 2の配置を応用してアミド窒素上に結合した水素が水素結合受 容基となって、 iSトリプターゼと水素結合する場合について、 もう 1組の特性球 を空間に配置した。  In addition, in the case where hydrogen bonded to the amide nitrogen becomes a hydrogen bond acceptor by applying the (2) -2 configuration and forms a hydrogen bond with iS tryptase, another pair of characteristic spheres are arranged in space. .
特性球として (DPositive Ionizable 、 ② Hydrophobic 、 ©Hydrogen -bond Donor 、 ④ Ring Aromaticの 4種類を用い、 それぞれ下記のような空間に配置し た。 ①化合物 Bのァミノメチル基の窒素原子を中心として半径 1 . 5人の球を置き、 Pos i t ive Ionizable に相当する特性球とした。 Four types of characteristic spheres (DPositive Ionizable, (2) Hydrophobic, © Hydrogen-bond Donor, and (4) Ring Aromatic were used and placed in the following spaces. (1) A sphere with a radius of 1.5 around the nitrogen atom of the aminomethyl group of compound B was placed, and a characteristic sphere equivalent to positive ionizable was set.
②ァミノメチルフエニル基のフェニル基の重心を中心として半径 1 . 5人の球を 置き、 Hydrophobi c に相当する特性球とした。  (2) A sphere with a radius of 1.5 was placed around the center of gravity of the phenyl group of the aminomethylphenyl group, and the characteristic sphere was equivalent to Hydrophobic.
③アミド結合の窒素原子を中心として半径 1 . 5人の球を置いた。 またアミド窒 素から窒素に結合した水素原子の方向に直線を引き、 3人離れた位置を中心とし て 2つ目の半径 1 . 5 Aの球を置いた。 これら 2つの球を Hydrogen— bond Donor に相当する特性球とした。 ③ A sphere with a radius of 1.5 was placed around the nitrogen atom of the amide bond. In addition, a straight line was drawn from the amide nitrogen to the hydrogen atom bonded to the nitrogen, and a second sphere with a radius of 1.5 A was placed centering on a position three people away. These two spheres were used as characteristic spheres equivalent to Hydrogen-bond Donor.
④ベンゾチォフェンのチォフェン環の重心を中心として半径 1 . 5人の球を置い た。 また、 この重心から芳香環平面に対して垂直な向きに直線を引き、 化合物 B から見て /3トリプ夕ーゼ側であり、 かつ上記の重心より 3 A離れた点を中心とし て 2つ目の半径 1 . 5人の球を置いた。 これら 2つの球を Ring Aromat icに相当 する特性球とした。  球 A 1.5-sphere ball was placed around the center of gravity of the benzothiophene thiophene ring. A straight line was drawn from this center of gravity in a direction perpendicular to the plane of the aromatic ring, and two points were located around the point of / 3 tripse seen from compound B and 3 A away from the center of gravity. Eye radius 1.5 Dropped balls. These two spheres were used as characteristic spheres equivalent to Ring Aromatics.
特性球の図を図 1 6に示す。  Figure 16 shows the characteristic sphere.
上記によって規定された化学的機能の 3次元空間上における相対的な位置関係 を表 1 1に記載した。 Table 11 shows the relative positional relationships in the three-dimensional space of the chemical functions defined above.
表 1 1 Table 11
化合物 Aの活性コンフオメーシヨンから得られたフアルマコフォア  Pharmacophore obtained from the active conformation of Compound A
Figure imgf000075_0001
化合物 Bの活性コンフオメーシヨンから得られたフアルマコフォア
Figure imgf000075_0001
Pharmacophore obtained from the active conformation of Compound B
くアミド酸素が水素結合受容基となって、 βトリプターゼと水素結合する場合 >  When the amide oxygen becomes a hydrogen bond acceptor and forms a hydrogen bond with β-tryptase>
Figure imgf000075_0002
Figure imgf000075_0002
<ァミド窒素が水素結合供与基となって、 Sトリプターゼと水素結合する場合〉 <When the amide nitrogen serves as a hydrogen bond donor and forms a hydrogen bond with S tryptase>
Figure imgf000075_0003
Figure imgf000075_0003
Catalys tに上記の通り設定し、 Catalys t用に変換した化合物デ一夕べ一スを用 いて、 両者の重ね合わせを行い、 評価関数で評価し、 ヒット化合物を選択した。 ヒッ 卜した化合物のうち、 後述する実施例化合物 3を表 1に記載のフアルマ コフォアに合致する （2 ) 一 1の例として、 後述する実施例化合物 6を表 2に記 載のフアルマコフォアに合致する ( 2 ) 一 2の例として、 後述する実施例化合物 4を表 2に記載のフアルマコフォアに合致する化合物 （2 ) — 3の例として バーチャルで選択し、 それぞれ後述する実施例を行った。 Catalyst was set as described above, and using the compound database converted for Catalyst, the two were superimposed, evaluated using an evaluation function, and a hit compound was selected. Of the hit compounds, Example Compound 3 described below matches the pharmacophore described in Table 1 (2) As an example, Example Compound 6 described below matches the pharmacophore described in Table 2 (2) As an example of (2), an example compound described later 4 was virtually selected as an example of the compound (2) -3 which matches the pharmacophore described in Table 2, and the examples described later were respectively performed.
(3) ヒト 3トリプ夕一ゼ活性を阻害する化合物の分子設計 (3) Molecular design of compounds that inhibit human 3-trippase activity
分子設計を実施するに当たり、 まず表 1または表 2に示したフアルマコフォア に合致する化合物の一般式を作成し、 下記のように表現した。  In carrying out the molecular design, first, a general formula of a compound matching the pharmacophore shown in Table 1 or Table 2 was created and expressed as follows.
一般式 S ,—L— Ar General formula S, —L— Ar
また、 各フラグメントの条件を以下のように設定した。  The conditions for each fragment were set as follows.
S , : S1ポケットに結合するフラグメントである。 例えば、 Aspl 89のカルボ キシル基と相互作用可能な （好ましくはイオン結合可能な） 窒素原子を有する置 換基をもつあるいは環構造に窒素を含む芳香環もしくは当該置換基をもつ環状炭 化水素を部分構造として含むフラグメント。 リンカ一への結合を想定して、 アル キレン基、 アミノ基、 力ルポニル基等が、 フラグメント基部に存在していること が好ましい。 このフラグメントは更にハロゲン、 炭素数 1〜3のアルキル基、 ァ ルコキシル基若しくはチォアルキル基、 力ルポキシル基、 または炭素数 2〜4の ァシル基若しくはカルボキシアルキル基などで置換されていても良い。  S,: A fragment that binds to the S1 pocket. For example, an aromatic ring having a nitrogen atom capable of interacting with (preferably ion-bonding with) a carboxyl group of Aspl 89, or an aromatic ring containing nitrogen in the ring structure, or a cyclic hydrocarbon having the substituent is used. Fragment to include as a partial structure. Assuming binding to a linker, it is preferable that an alkylene group, an amino group, a sulfonyl group, and the like be present in the fragment base. This fragment may be further substituted with halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxyl or thioalkyl group, a propyloxyl group, or an acryl or carboxyalkyl group having 2 to 4 carbon atoms.
L : S ,と Arを結合するリンカー部位  L: Linker site that connects S, and Ar
S 1と Arの双方を連結するフラグメントであり、 フアルマコフォアに合致する分 子の立体配座を維持できるもの。 例えば、 リンカ一内部に、 窒素、 酸素、 硫黄か ら選ばれるヘテロ原子 1個ないし 3個 （好ましくは窒素原子 1個ないし 2個） お よび炭素数 1個ないし 5個を有する直鎖もしくは環状の炭化水素基が挙げら れる。 当該炭化水素基は、 更に、 炭素数 1〜3のアルキル基、 アルコキシル基、 チォアルキル基若しくはアルキルスルホニル基、 力ルポキシル基、 または炭素数 2 4のァシル基若しくはカルポキシアルキル基またはォキソ基等の置換基を有 していても良い。 リンカ一の端部は、 および A rのフラグメントへの結合を 想定して、 イミノ基、 アルキレン基、 カルポニル基であることが好ましい。 Is a fragment which connects both S 1 and Ar, which can maintain the conformation of-molecular matching the Fuarumakofoa. For example, a linear or cyclic linker having 1 to 3 hetero atoms (preferably 1 to 2 nitrogen atoms) and 1 to 5 carbon atoms selected from nitrogen, oxygen, and sulfur inside the linker. And a hydrocarbon group. The hydrocarbon group further includes an alkyl group having 1 to 3 carbon atoms, an alkoxyl group, a thioalkyl group or an alkylsulfonyl group, a lipoxyl group, or a carbon number. It may have 24 substituents such as an acyl group, a carboxyalkyl group or an oxo group. The end of the linker is preferably an imino group, an alkylene group, or a carbonyl group, assuming the binding of and to the fragment of Ar.
Ar : 芳香環  Ar: aromatic ring
芳香環または環状炭化水素を基本構造に持つフラグメント。 好ましくは、 構成 員数 5ないし 1 4の単環、 縮環もしくは縮合 3環を有し、 環内に窒素、 酸素、 硫 黄などのへテロ原子が含まれていても良い。 特に好ましくはナフタレン環などの 2環性芳香環である。 リンカ一への結合を想定して、 スルホニル基、 カルポニル 基、 アルキレン基等がフラグメント基部に存在していることが好ましい。 また芳 香環または環状炭ィ匕水素はハロゲン、 炭素数 1 3のアルキル基、 アルコキシル 基若しくはチォアルキル基、 力ルポキシル基、 炭素数 2 4のァシル基若しくは カルポキシアルキル基、 ォキソ基またはアミノ基などで置換されていても良い。  A fragment having an aromatic ring or cyclic hydrocarbon as its basic structure. It preferably has a monocyclic, condensed or condensed tricyclic ring having 5 to 14 members, and may contain a hetero atom such as nitrogen, oxygen, or sulfur in the ring. Particularly preferred is a bicyclic aromatic ring such as a naphthalene ring. Assuming a bond to a linker, it is preferable that a sulfonyl group, a carbonyl group, an alkylene group and the like are present in the fragment group. The aromatic ring or cyclic hydrogen is a halogen, an alkyl group having 13 carbon atoms, an alkoxyl group or a thioalkyl group, a propyloxyl group, an acyl group or a carboxyalkyl group having 24 carbon atoms, an oxo group or an amino group. May be substituted.
S L Arとして用いることができるフラグメントは、 あらかじめ準 備したコンピュータスクリーニング用の化合物構造デー夕べ一スを対象として、 望ましい部分構造を収集した。 、 Lに該当するフラグメントの例を表 3に、 A rに該当するフラグメントの例を表 4にそれぞれ示した。 As for fragments that can be used as SL Ar, desirable partial structures were collected from a compound structure database for computer screening prepared in advance. Table 3 shows examples of fragments corresponding to L and L, and Table 4 shows examples of fragments corresponding to Ar.
Figure imgf000078_0001
Figure imgf000078_0001
s s
Figure imgf000078_0002
Figure imgf000078_0002
s辇 s 辇
L LL L
£Z.600/£00idf/X3d 表 4 £ Z.600 / £ 00idf / X3d Table 4
Figure imgf000079_0001
Figure imgf000079_0001
NH, X = {NH, 0, S} 分子設計用ソフトウェアとして Sybyl (トライボス社) のモジュールであ る CombiLibMaker を使用した。 Sい L 、 Αι'に相当するフラグメントデータベース を CombiLibMaker に入力し、 それらの組み合わせによって新規化合物を二次元構 造としてコンピュータ上で生成させた。 この初期構造を三次元構造発生プロダラ ム CORINA (Mo l ecul ar Networks GmbH Comput erchemi e社） を用いて三次元化し、 Dockに入力して Dock用データベースに変換した。 また二次元構造を Catalys tに入 力し、 最安定配座より 2 O kcal/molを生成エネルギーの上限として立体配座を自 動発生させ、 Catalys t用データベースに変換した。 実施例 6で述べたフアルマコ フォアとこれらのデ一夕べ一スを用いて Dock若しくは Cat al ys tを用いたコン ピュータスクリーニングを実施した。 Dockの場合は評価関数のスコア値と結合状 態を目視することにより、 両者を総合的に判断してヒット化合物を選択した。 ま た Catalys tの場合は評価関数の値がある値以下の化合物をヒッ卜化合物として選 択した。 これらのコンピュータスクリーニングを併用し、 「活性コンフォ メ一シヨンを利用したフアルマコフォア」 を充足する化合物を選択した。 選択し た化合物のうち、 後述する実施例化合物 7、 8、 9を表 1に記載のフアルマ コフォアに合致する化合物の例として、 後述する実施例化合物 1 0、 1 1を表 2 に記載のフアルマコフォアに合致する化合物の例として、 それぞれ後述する実施 例を行った。 NH, X = {NH, 0, S} CombiLibMaker, a module of Sybyl (Tribos), was used as molecular design software. Enter the fragment database corresponding to S, L, Αι 'into CombiLibMaker, and create a new compound in a two-dimensional structure by combining them. Was generated on a computer. This initial structure was converted into a three-dimensional structure using the three-dimensional structure generation program CORINA (Molecular Networks GmbH Computerchemie), and input to the Dock and converted to a Dock database. In addition, the two-dimensional structure was input to Catalyst, and the conformation was automatically generated from the most stable conformation with the upper limit of the generation energy of 2 kcal / mol, and converted to a Catalyst database. Using the pharmacophores described in Example 6 and their data overnight, computer screening was performed using Dock or Catalyst. In the case of the Dock, the hit compound was selected by visually judging the score value of the evaluation function and the binding state, and comprehensively judging both. In the case of Catalys, a compound having a value of the evaluation function equal to or less than a certain value was selected as a hit compound. By using these computer screenings in combination, a compound satisfying the “pharmacophore using active conformation” was selected. Of the selected compounds, Example Compounds 7, 8, and 9 described below are examples of compounds that match the pharmacophores described in Table 1, and Example Compounds 10 and 11 described below are pharmacophores described in Table 2. As examples of compounds that conform to the following, Examples described later were performed.
実施例化合物の構造式を表 1 2に示す。 なお、 実施例化合物 1は化合物 A、 実 施例化合物 2は化合物 Bである。  Table 12 shows the structural formulas of the example compounds. In addition, Example Compound 1 is Compound A, and Example Compound 2 is Compound B.
実施例化合物 1から実施例化合物 1 2の構造式を表 1 2に示す。 表 12 Table 12 shows the structural formulas of Example Compound 1 to Example Compound 12. Table 12
実施例化合物 1 実施例化合物 7  Example compound 1 Example compound 7
CF3C02HCF 3 C0 2 H
Figure imgf000081_0001
Figure imgf000081_0001
実施例化合物 3 実施例化合物 9
Figure imgf000081_0002
Example compound 3 Example compound 9
Figure imgf000081_0002
実施例化合物 4 実施例化合物 1 o  Example compound 4 Example compound 1 o
Figure imgf000081_0003
Figure imgf000081_0003
実施例化合物 6 実施例化合物 1 2
Figure imgf000081_0004
実施例 8 化合物の合成 Example compound 6 Example compound 1 2
Figure imgf000081_0004
Example 8 Synthesis of compound
化合物 A (実施例化合物 1 ) 、 化合物 B (実施例化合物 2 ) 及び実施例 7の結 果選択された実施例化合物 3〜12の合成法について以下に述べる。 なお、 化合 物 A (実施例化合物 1 ) 、 化合物 B (実施例化合物 2) についても、 実施例 7 ( 1) 及び （2) の方法にてヒットした。 Compound A (Example Compound 1), Compound B (Example Compound 2) and the results of Example 7 The synthesis method of the selected Example Compounds 3 to 12 is described below. Compound A (Example Compound 1) and Compound B (Example Compound 2) were also hit by the methods of Examples 7 (1) and (2).
核磁気共鳴 （NMR) スペクトルはジェオル JNM— EX270 (J EOLJ NM-EX270) FT— NMR (データに *を表示、 日本電子 （株） 製） また はジェオル J NM—LA 300 (J EOL JNM-LA300) FT— NMR (日本電子 （株） 製） を用いて測定した。  The nuclear magnetic resonance (NMR) spectrum is JEOL JNM-EX270 (J EOLJ NM-EX270) FT-NMR (* is shown on the data, manufactured by JEOL Ltd.) or JEOL J NM-LA300 (J EOL JNM-LA300) ) Measured using FT-NMR (manufactured by JEOL Ltd.).
(実施例化合物 1の合成）  (Synthesis of Example Compound 1)
N— [2- [N— [3— [4一 (アミノメチル) フエニル] プロピル] ァミノ] ェチル] 一 2—ナフ夕レンスルホンアミドの合成 N— [2- [N— [3 -— [4- (Aminomethyl) phenyl] propyl] amino] ethyl] Synthesis of 1-2-naphthylenesulfonamide
く工程 1 > 3— [4- (N— t e r t一ブトキシカルポニルアミノメチル) フエニル] プロパナールの合成  Step 1> Synthesis of 3 -— [4- (N-tert-butoxycarbonylaminomethyl) phenyl] propanal
4— (N— t e r t一ブトキシカルボニルァミノメチル) — 1—ョ一ドベンゼン ( 1. 32 g) のァセトニトリル ( 2 0 mL) 溶液に、 ァリルアルコール (0. 35g) 、 酢酸パラジウム （II) (17. 8mg) 、 炭酸水素ナトリウム (0. 83 g) およびテトラプチルアンモニゥムクロリ ド （1. 10 g) を 加え、 1. 5時間加熱還流した。 放冷後、 反応液に水を加えて酢酸ェチルにて抽 出した。 水および飽和食塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 減圧下溶媒 を留去した。 得られた残渣をシリカゲルカラムクロマトグラフィー （溶出 溶媒； 酢酸ェチル ： へキサン == 3 ： 1) で精製することにより標記化合物 ( 0. 93 g、 実施例化合物中間体番号 1一 1 ) を得た。  To a solution of 4- (N-tert-butoxycarbonylaminomethyl) -l-odobenzene (1.32 g) in acetonitrile (20 mL), aryl alcohol (0.35 g), palladium (II) acetate (II) 17.8 mg), sodium hydrogencarbonate (0.83 g) and tetrabutylammonium chloride (1.10 g) were added, and the mixture was heated under reflux for 1.5 hours. After cooling, water was added to the reaction solution, and extracted with ethyl acetate. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: hexane == 3: 1) to give the title compound (0.93 g, Example compound intermediate No. 11-11) .
く工程 2> N— [2— [N— [3— [4- (N— t e r t—ブトキシカルボ P2003/009738 Step 2> N— [2— [N— [3— [4- (N—tert—butoxycarbo P2003 / 009738
82  82
ニルアミノメチル) フエニル] プロピル] ァミノ] ェチル] 一 2—ナフ夕レンス ルホンアミドの合成 Nylaminomethyl) phenyl] propyl] amino] ethyl] Synthesis of 2-naphthylene sulphonamide
工程 1で得られた化合物 （0. 15 g) の塩化メチレン （3mL) 溶液に N— (2—アミノエチル） 一 2一ナフ夕レンスルホンアミド (0. 14 g) 、 モレキ ユラシーブス 3 A (粉末； 0. 15 g) 、 次いで酢酸 （33 L) を加えた。 窒 素雰囲気下室温で 30分間攪拌後、 トリァセトキシ水素化ホウ素ナトリウム (0. 18 g) を加え、 室温で一夜攪拌した。 反応液に水を加え、 1規定水酸化 ナトリウム水溶液を加えてアルカリ性とし、 塩化メチレンにて抽出した。 水およ び飽和食塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去した。 得 られた残渣をシリ力ゲル力ラムクロマトグラフィー [クロマトレックス NHTM；To a solution of the compound (0.15 g) obtained in Step 1 in methylene chloride (3 mL) was added N- (2-aminoethyl) -121-naphthylene sulphonamide (0.14 g), Moleki Eurasheaves 3 A (powder 0.15 g) followed by acetic acid (33 L). After stirring at room temperature for 30 minutes in a nitrogen atmosphere, sodium triacetoxyborohydride (0.18 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was basified with a 1N aqueous sodium hydroxide solution and extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to gel chromatography on silica gel [Chromatrex NH ™ ;
C h r oma t o r e xNH™] (溶出溶媒；塩化メチレン： メタノール =ChromatoorexNH ™] (Eluent: methylene chloride: methanol =
100： 1〜10 ： 1) で精製することにより標記化合物 （0. 05 g、 実施例 化合物中間体番号 1一 2) を得た。 Purification by 100: 1 to 10: 1) gave the title compound (0.05 g, Example compound intermediate No. 1-2).
く工程 3> N— [2— [N- [3— [4一 （アミノメチル） フエニル] プロピ ル] ァミノ] ェチル] 一 2—ナフ夕レンスルホンアミドの合成 Step 3> Synthesis of N— [2-—N- [3 -— [4- (aminomethyl) phenyl] propyl] amino] ethyl] -12-naphthylenesulfonamide
工程 2で得られた化合物 (23. 9mg) にァニソール (26 L) 、 次いで 氷水冷下トリフルォロ酢酸 （2. 4mL) を加え、 窒素雰囲気下、 室温で一夜攪 拌した。 反応液に水を加え、 1規定水酸化ナトリウム水溶液を加えてアルカリ性 とし、 塩化メチレンにて抽出した。 水および飽和食塩水で洗浄、 無水硫酸ナトリ ゥムで乾燥後、 減圧下溶媒を留去した。 得られた残渣をシリカゲルカラムクロマ トグラフィー [クロマトレックス NHTM； C h r o m t o r e x H™] (溶 出溶媒；塩化メチレン： メタノール =100 ： 1〜10 ： 1) で精製することに より標記化合物 （11. 2mg) を得た。 To the compound (23.9 mg) obtained in Step 2 were added anisol (26 L) and then trifluoroacetic acid (2.4 mL) under ice-cooling, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction solution was added with water, made alkaline with a 1N aqueous solution of sodium hydroxide, and extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Chromatorex NH ™ ; Chromtorex H ™] (eluting solvent: methylene chloride: methanol = 100: 1 to 10: 1). Thus, the title compound (11.2 mg) was obtained.
(実施例化合物 2の合成）  (Synthesis of Example Compound 2)
N- [2- [N— [3— [4— (アミノメチル) フエニル] プロピル] — N—メ チルァミノ] ェチル] —2—ベンゾ [ID] チォフェン力ルポキサミドニ塩酸塩の 合成 N- [2- [N— [3 -— [4- (Aminomethyl) phenyl] propyl] —N-methylamino] ethyl] —2-benzo [ID] Synthesis of thiophene lipoxamidini hydrochloride
く工程 1〉 N— (9一フルォレニルメトキシカルボニル) -N- [2- [N 一 [3- [4— (N— t e r t—ブトキシカルボニルアミノメチル） フエニル] プロピル] 一 N—メチルァミノ] ェチル] ァミンの合成  Step 1> N- (9-Fluorenylmethoxycarbonyl) -N- [2- [N- [3- [4- (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] -N-methylamino] Synthesis of Amin
実施例化合物 1の合成の工程 1で得られた化合物 （2. 8 g) の無水塩化メチ レン （15mL) 溶液に N— （ 9一フルォレニルメトキシカルポニル） 一 N— [ 2— （メチルァミノ） ェチル] ァミン塩酸塩 （3. 6 g) 、 次いでトリァセトキ シ水素化ホウ素ナトリウム （4. 6 g) を加え、 窒素雰囲気下室温で一夜攪拌し た。 反応液に飽和重曹水を加えてアルカリ性とし、 塩化メチレンで抽出した。 水 および飽和食塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去 した。 得られた残渣をシリカゲルカラムクロマトグラフィー （溶出溶媒；塩ィ匕メ チレン：メタノール =20 ： 1) で精製することにより標記化合物 （4. 1 g、 実施例化合物中間体番号 2— 1 ) を得た。  To a solution of the compound (2.8 g) obtained in Step 1 of the synthesis of Example Compound 1 in anhydrous methylene chloride (15 mL) was added N- (9-fluorenylmethoxycarbonyl) -N- [2- (methylamino ) Ethyl] amine hydrochloride (3.6 g) and then sodium triacetoxyborohydride (4.6 g) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction solution was made alkaline by adding saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: Shii-Dai-Methylene: Methanol = 20: 1) to give the title compound (4.1 g, Example compound intermediate 2-1). Was.
く工程 2 > 2― [N- [3— [4一 (N- t e r t—ブトキシカルボニルァ ミノメチル） フエニル] プロピル] 一 N—メチルァミノ] ェチルアミンの合成 工程 1で得られた化合物 （4. 1 g) に、 モルホリン （20mL) を加え、 室 温で 4時間攪拌した。 反応液に水を加え、 塩化メチレンで抽出した。 水および飽 和食塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去した。 得られ た残渣をシリカゲルカラムクロマトグラフィー （溶出溶媒；塩化メチレン：メタ ノール =3 ： 1〜1 ： 1) で精製することにより標記化合物 （1. 5 g、 実施例 化合物中間体番号 2— 2) を得た。 ' Step 2> Synthesis of 2- [N- [3 -— [4-1 (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] -N-methylamino] ethylamine Compound obtained in Step 1 (4.1 g) To the mixture was added morpholine (20 mL), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Obtained The residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 3: 1 to 1: 1) to give the title compound (1.5 g, Example compound intermediate number 2-2) Was. '
く工程 3〉 N— [2— [N- [3— [4- (N— t e r t—ブトキシカルポ ニルアミノメチル） フエニル] プロピル] 一 N—メチルァミノ] ェチル] 一 2— ベンゾ [b] チォフェンカルポキサミドの合成  Step 3> N— [2— [N- [3-—4- (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] -1-N-methylamino] ethyl] -1-2-benzo [b] thiophencarpoxa Synthesis of mid
ベンゾ [b] チォフェン—2—カルボン酸 （18. 3mg) の塩化メチレン （ 2mL) 溶液に、 1ーェチルー 3— (3—ジメチルァミノプロピル） カルポジィ ミド塩酸塩 （21. 5mg) および工程 2で得られた化合物 （30. Omg) を 加え、 室温で一夜攪拌した。 反応液に水を加え、 塩化メチレンで抽出した。 水お よび飽和食塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去した。 得られた残渣をシリカゲルカラムクロマトグラフィー （溶出溶媒；酢酸ェチル： へキサン = 1 ； i、 次に酢酸ェチル） で精製することにより標記化合物 （ To a solution of benzo [b] thiophene-2-carboxylic acid (18.3 mg) in methylene chloride (2 mL) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (21.5 mg) and the product obtained in Step 2. The obtained compound (30. Omg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: hexane = 1; i, then ethyl acetate) to give the title compound (
34. 8mg、 実施例化合物中間体番号 2— 3) を得た。 34.8 mg, Example compound intermediate number 2-3) was obtained.
く工程 4〉 N— [2 - [N— [3— [4- (アミノメチル) フエニル] プロ ピル] 一 N—メチルァミノ] ェチル] 一 2—べンゾ [b] チォフェンカルボキサ ミドニ塩酸塩の合成  Step 4> N— [2- [N— [3 -— [4- (aminomethyl) phenyl] propyl] -1-N-methylamino] ethyl] -12-benzo [b] thiophencarboxamidoni hydrochloride Synthesis of
工程 3で得られた化合物 （30. Omg) の酢酸ェチル （3mL) 溶液に、 飽 和塩化水素一酢酸ェチル （3mL) を加えて、 室温で 2時間攪拌した。 析出した 沈殿物をろ取し、 エーテルで洗浄することにより標記化合物 （23. Omg) を 得た。  To a solution of the compound (30. Omg) obtained in Step 3 in ethyl acetate (3 mL) was added saturated hydrogen chloride monoethyl acetate (3 mL), and the mixture was stirred at room temperature for 2 hours. The deposited precipitate was collected by filtration and washed with ether to give the title compound (23. Omg).
' (実施例化合物 3の合成） N— [1— [4- (アミノメチル） フエニル] ピぺリジン一 4—ィル] — N— [1— [4- (アミノメチル) フエニル] ピぺリジン一 4—ィルメチル] ァセト アミドの合成 '' (Synthesis of Example Compound 3) Synthesis of N— [1— [4- (Aminomethyl) phenyl] piperidin-1-yl] —N— [1— [4- (Aminomethyl) phenyl] piperidin-1-4-ylmethyl] acetamide
く工程 1 > [1— [4一 （N— t e r t—ブトキシカルポニルァミノメチル ) フエニル] ピぺリジン一 4一ィル] 一 [1— [4一 （Ν— t e r t—ブトキシ カルポニルアミノメチル) フエニル] ピぺリジン一4—ィルメチル] ァミンの合 成  Step 1> [1- [4-I- (N-tert-butoxycarbonylaminomethyl) phenyl] piperidine-1 4-yl] -1 [1- [4-1 (一 -tert-butoxycarbonylaminomethyl) phenyl ] Synthesis of piperidine-1-ylmethyl] amine
4—アミノー 1一 [4- (N— t e r t—ブトキシカルポニルアミノメチル) フエニル] ピぺリジン （0. 40 g) および 1— [4_ (N— t e r t—ブトキ シカルポエルアミノメチル） フエニル] 一 4—ピペリジンカルバルデヒド (0. 58 g) を用いて、 実施例化合物 1の合成の工程 2と同様の方法で反応を 行い、 標記化合物 （0. 62 g、 実施例化合物中間体番号 3— 1) を得た。  4-amino-11- [4- (N-tert-butoxycarbonylaminomethyl) phenyl] piperidine (0.40 g) and 1- [4_ (N-tert-butoxycarpoylaminomethyl) phenyl] -1-4- Using piperidine carbaldehyde (0.58 g), the reaction was carried out in the same manner as in Step 2 of the synthesis of Example Compound 1, and the title compound (0.62 g, Example Compound Intermediate No. 3-1) was obtained. Obtained.
<工程 2> N- C 1一 [4一 (N- t e r t—ブトキシカルポニルアミノメ チル） フエニル] ピぺリジン一 4—ィル] -N- [1— [4- (N— t e r t— ブ卜キシカルボニルアミノメチル) フエニル] ピぺリジン一 4一ィルメチル] ァ セトアミドの合成  <Step 2> N-C1- [4- (N-tert-butoxycarbonylaminomethyl) phenyl] piperidin-4-yl] -N- [1- (4- (N-tert-butyrate) Synthesis of xycarbonylaminomethyl) phenyl] piperidine-4-ylmethyl] acetoamide
工程 1で得られた化合物 （0. 30 g) の塩化メチレン （10mL) 溶液にト リエチルァミン （69 L) 、 次いで氷水冷下ァセチルク口リド (37 L) 加 え、 室温で 10分間攪拌した。 反応液を水に注ぎ、 塩化メチレンにて抽出した。 水および飽和食塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去す ることにより標記化合物 （0. 34 g、 実施例化合物中間体番号 3— 2) を 得た。 く工程 3 > N— [1 - [4— (アミノメチル) フエニル] ピぺリジン一 4一 ィル] — N— [1- [4- (アミノメチル） フエニル] ピぺリジン一 4—ィルメ チル] ァセトアミドの合成 To a solution of the compound obtained in step 1 (0.30 g) in methylene chloride (10 mL) were added triethylamine (69 L) and then acetyl chloride (37 L) under ice-water cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was poured into water and extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (0.34 g, Intermediate No. 2-2 of Example compound). Step 3> N— [1- [4- (Aminomethyl) phenyl] piperidin-1-yl] — N— [1- [4- (Aminomethyl) phenyl] piperidin-1-4-ylmethyl ] Synthesis of acetoamide
工程 2で得られた化合物 （0. 10g) を用いて、 実施例化合物 1の合成のェ 程 3と同様の方法で反応を行い、 標記化合物 （59. 3mg) を得た。  Using the compound (0.10 g) obtained in Step 2, the reaction was carried out in the same manner as in Step 3 of the synthesis of Example Compound 1 to give the title compound (59.3 mg).
(実施例化合物 4の合成）  (Synthesis of Example Compound 4)
ビス [3- [4一 (アミノメチル) フエニル] プロピル] 一 （2—アミノエチ ル） ァミンの合成  Synthesis of bis [3- [4- (aminomethyl) phenyl] propyl]-(2-aminoethyl) amine
く工程 1 > N— [2— [ビス [3— [4- (N— t e r t—ブトキシカルポ ニルアミノメチル） フエニル] プロピル] ァミノ] ェチル] トリフルォロアセト アミドの合成  Step 1> Synthesis of N— [2-—bis [3- [4- (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] amino] ethyl] trifluoroacetamide
実施例化合物 1の合成の工程 1で得られた化合物 （ 0. 16 g ) および N— ( 2—ァミノェチル） トリフルォロアセトアミ ド塩酸塩 （5 9. Omg) を 用いて、 実施例化合物 2の合成の工程 1と同様の方法で反応を行い、 標記化合物 ( 0. 14 g、 実施例化合物中間体番号 4一 1 ) を得た。  Example Compound 2 was prepared using the compound (0.16 g) obtained in Step 1 of the synthesis of Example Compound 1 and N- (2-aminoethyl) trifluoroacetamide hydrochloride (59.Omg). The reaction was conducted in the same manner as in Step 1 of the synthesis of, to obtain the title compound (0.14 g, Example compound intermediate number 411).
く工程 2 > ビス [3— [4— (N- t e r t一ブトキシカルポニルアミノメ チル) フエニル] プロピル] ― (2—アミノエチル) ァミンの合成  Step 2> Synthesis of bis [3 -— [4 -— (N-tert-butoxycarbonylaminomethyl) phenyl] propyl]-(2-aminoethyl) amine
工程 1で得られた化合物 （0. 14g) のメタノール （9mL) 溶液に、 炭酸 カリウム （0. 1 5 ) 水溶液 （0. 5mL) を加え、 1. 5時間加熱還流 した。 反応液を減圧下溶媒を留去し、 残渣に水を加え、 塩化メチレンにて抽出し た。 水および飽和食塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 減圧下溶媒を留 去した。 得られた残渣をシリカゲルカラムクロマトグラフィー [クロマトレック ス NHTM； Ch r oma t o r e xNH™] (溶出溶媒；塩化メチレン ： メタノール =100 : 1) で精製することにより標記化合物 （78. 0mg、 実 施例化合物中間体番号 4一 2) を得た。 To a solution of the compound (0.14 g) obtained in Step 1 in methanol (9 mL) was added an aqueous solution of potassium carbonate (0.15) (0.5 mL), and the mixture was heated under reflux for 1.5 hours. The solvent was distilled off from the reaction solution under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue is subjected to silica gel column chromatography [Chromatreck Scan NH TM; Ch r oma tore xNH ™] ( eluent; methylene chloride: methanol = 100: 1) to give the title compound (78. 0 mg, actual施例compound Intermediate No. 4 one 2) to give .
く工程 3> ビス [3- [4一 (アミノメチル) フエニル] プロピル] 一 (2 一アミノエチル) ァミンの合成  Step 3> Synthesis of bis [3- [4- (aminomethyl) phenyl] propyl]-(2-aminoethyl) amine
工程 2で得られた化合物 （78. Omg) の酢酸ェチル （5mL) 溶液に飽和 塩化水素—酢酸ェチル溶液 （lmL) を加え、 室温で 2時間攪拌した。 析出物を ろ取し、 酢酸ェチルで洗浄し、 塩化メチレンおよび 1規定水酸化ナトリウム水溶 液を加え、 塩化メチレンにて抽出した。 水および飽和食塩水で洗浄、 無水硫酸ナ トリウムで乾燥後、 減圧下溶媒.を留去することにより標記化合物 （46. 3mg ) を得た。  To a solution of the compound (78. Omg) obtained in Step 2 in ethyl acetate (5 mL) was added a saturated hydrogen chloride-ethyl acetate solution (1 mL), and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with ethyl acetate, methylene chloride and a 1N aqueous solution of sodium hydroxide were added, and the mixture was extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (46.3 mg).
(実施例化合物 5の合成）  (Synthesis of Example Compound 5)
N— [ 2 - [N— [2— [4 - (アミノメチル) フエノキシ] ェチル] ァミノ] ェチル] 一 2—ナフタレンスルホンアミドの合成  Synthesis of N- [2- [N- [2- (4- [aminomethyl) phenoxy] ethyl] amino] ethyl] -2-naphthalenesulfonamide
く工程 1 > N— [2 - (2—ナフタレンスルホニルァミノ) ェチル] 一 (4 ーシァノフエノキシ) ァセトアミドの合成  Step 1> Synthesis of N— [2- (2-naphthalenesulfonylamino) ethyl] 1- (4-cyanophenoxy) acetamide
(4—シァノフエノキシ） 酢酸リチウム塩 （ 1. 00 g) の塩化メチレン (2 OmL) 懸濁液に 1M塩化水素—エーテル溶液 （4. 64mL) 、 1—ェチ ル一3— (3—ジメチルァミノプロピル） カルポジイミド塩酸塩 (1. 59 g) および N— (2—アミノエチル） 一 2—ナフタレンスルホンアミド （1. 16 g ) を加え、 室温で 30分間攪拌した。 反応液に水を加え、 1規定水酸化ナトリウ ム水溶液を加えてアル力リ性とし、 クロ口ホルムを加えて攪拌した。 セライトを 用いてろ過し、 ろ液をクロ口ホルムで抽出した。 水および飽和食塩水で洗浄、 無 水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去した。 得られた残渣にエーテル Z へキサンを加え、 ろ過することにより標記化合物 （1. 31 g、 実施例化合物中 間体番号 5— 1) を得た。 To a suspension of (4-cyanophenoxy) acetic acid lithium salt (1.00 g) in methylene chloride (2 OmL) was added a 1M hydrogen chloride-ether solution (4.64 mL), and 1-ethyl-3- (3-dimethyla). (Minopropyl) carbodiimide hydrochloride (1.59 g) and N- (2-aminoethyl) -12-naphthalenesulfonamide (1.16 g) were added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and a 1N aqueous solution of sodium hydroxide was added to make the solution more viscous. Celite The filtrate was extracted with black-mouthed form. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Ether Z hexane was added to the obtained residue, and the mixture was filtered to give the title compound (1.31 g, Intermediate No. 5-1 of Example compound).
く工程 2> N— [2- [N- [2— [4- (アミノメチル) フエノキシ] ェ チル] ァミノ] ェチル] 一 2—ナフタレンスルホンアミドの合成  Step 2> Synthesis of N— [2- [N- [2 -— [4- (aminomethyl) phenoxy] ethyl] amino] ethyl] -1-2-naphthalenesulfonamide
工程 2で得られた化合物 （0. 20 g) のテトラヒドロフラン （5mL) 溶液 にポランーテトラヒドロフラン錯塩テトラヒドロフラン溶液 (1M； 4. 88m L) を加え、 30分間加熱還流した。 氷水冷下メタノールを加え、 さらに 10% 塩化水素—メタノール溶液 （5mL) を加えて 30分間加熱還流した。 反応液を 減圧下溶媒留去し、 残渣に水および 1規定水酸化ナトリゥム水溶液を加えてアル カリ性とし、 塩化メチレンで抽出した。 水および飽和食塩水で洗浄、 無水硫酸ナ トリウムで乾燥後、 減圧下溶媒を留去した。 得られた残渣を 1, 4一ジォキサン (2mL) に溶解し二炭酸ジー t e r t—ブチル （153. Omg) および炭酸 ナトリウム水溶液 （1M ; 0· 88mL) を加え、 60 °Cで 5分間撹拌した。 反 応液に水を加え、 塩化メチレンにて抽出した。 水および飽和食塩水で洗浄、 無水 硫酸ナトリウムで乾燥後、 減圧下溶媒を留去した。 得られた残渣をシリカゲル力 ラムクロマトグラフィー （溶出溶媒；酢酸ェチル：へキサン = 1 ： 4) で精製し た。 得られた化合物を実施例化合物 1の合成の工程 3と同様の方法で処理するこ とにより標記化合物 （46. 7mg) を得た。  To a solution of the compound (0.20 g) obtained in Step 2 in tetrahydrofuran (5 mL) was added a solution of porane-tetrahydrofuran complex salt in tetrahydrofuran (1 M; 4.88 mL), and the mixture was heated under reflux for 30 minutes. Under ice-cooling, methanol was added, and a 10% hydrogen chloride-methanol solution (5 mL) was further added, followed by heating under reflux for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was made alkaline by adding water and a 1N aqueous solution of sodium hydroxide, and extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (2 mL), di-tert-butyl dicarbonate (153. Omg) and an aqueous sodium carbonate solution (1 M; 0.88 mL) were added, and the mixture was stirred at 60 ° C for 5 minutes. Water was added to the reaction solution, and extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: hexane = 1: 4). The obtained compound was treated in the same manner as in Step 3 of the synthesis of Example Compound 1 to give the title compound (46.7 mg).
(実施例化合物 6の合成）  (Synthesis of Example Compound 6)
N- [2— [N— [3— [4- (アミノメチル） フエニル] プロパノィル] 一 P T/JP2003/009738 N- [2— [N— [3 -— [4- (aminomethyl) phenyl] propanoyl] PT / JP2003 / 009738
89  89
N—メチルァミノ] ェチル] 一 2—べンゾ [b] チォフェンカルポキサミド塩酸 塩の合成  Synthesis of N-methylamino] ethyl] 1-2-benzo [b] thiophencarpoxamide hydrochloride
工程 1〉 3— [4一 （N— t e r t—ブトキシカルポニルアミノメチル） フエニル] プロピオン酸リチウム塩の合成  Step 1> Synthesis of 3- [4- (N-tert-butoxycarbonylaminomethyl) phenyl] lithium propionate
3— [4- (N- t e r t一ブトキシカルポニルアミノメチル) フエニル] プ ロピオン酸ェチルエステル （4. 06 g) のメタノール （1 7mL) 溶液に 水酸化リチウム '一水和物 （0. 55 g) の水溶液 （7mL) を加え、 20分間 60°Cで加熱攪拌した。 反応液を減圧下溶媒を留去した。 得られた残渣に トルエンを加え、 減圧下溶媒を留去した。 得られた残渣にへキサンを加え、 ろ過 することにより標記化合物 （ 3. 38 g、 実施例化合物中間体番号 6— 1 ) を得 た。  3 -— [4- (N-tert-Butoxycarbonylaminomethyl) phenyl] ethyl propionate (4.06 g) in methanol (17 mL) solution of lithium hydroxide 'monohydrate (0.55 g) An aqueous solution (7 mL) was added, and the mixture was heated with stirring at 60 ° C for 20 minutes. The solvent was distilled off from the reaction solution under reduced pressure. Toluene was added to the obtained residue, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, followed by filtration to obtain the title compound (3.38 g, Example compound intermediate No. 6-1).
く工程 2〉 N— [2— (N— t e r t—ブトキシカルボ二ルー N—メチルァ ミノ） ェチル] 一 2—ベンゾ [b] チォフェンカルポキサミドの合成  Step 2> Synthesis of N— [2 -— (N-tert-butoxycarbonyl N-methylamino) ethyl] -12-benzo [b] thiophencarpoxamide
ベンゾ [b] チォフェン一 2—力ルボン酸 （1. 53 g) および 2— (N- t e r t一ブトキシカルボ二ルー N—メチルァミノ) ェチルァミン (1. 0 g) を 用いて、 実施例化合物 2の合成の工程 3と同様の方法で反応を行い、 標記化合物 ( 1. 86 g、 実施例化合物中間体番号 6— 2 ) を得た。  Synthesis of Example Compound 2 using benzo [b] thiophene-2-fluorocarboxylic acid (1.53 g) and 2- (N-tert-butoxycarbonyl N-methylamino) ethylamine (1.0 g) The reaction was carried out in the same manner as in Step 3 of Step 3 to obtain the title compound (1.86 g, Example compound intermediate No. 6-2).
く工程 3〉 N- [ 2 - (メチルァミノ） ェチル] 一 2—ベンゾ [b] チォフェン力ルポキサミド塩酸塩の合成  Step 3> Synthesis of N- [2- (methylamino) ethyl] -1-2-benzo [b] thiophene-L-Lupoxamide Hydrochloride
工程 2で得られた化合物 （1. 81 ) を用いて、 実施例化合物 2の合成のェ 程 4と同様の方法で反 を行い、 標記化合物 （1. 31 g、 実施例化合物中間体 番号 6— 3) を得た。 <工程 4> N— [2- [N— [3— [4— (N— t e r t—ブトキシカルポ ニルアミノメチル） フエニル] プロパノィル] 一 N—メチルァミノ] ェチル] 一 2—ベンゾ [b] チォフェンカルポキサミドの合成 Using the compound (1.81) obtained in Step 2, the reaction was carried out in the same manner as in Step 4 of the synthesis of Example Compound 2, to give the title compound (1.31 g, Example Compound Intermediate No. 6) — 3) <Step 4> N— [2- [N— [3-—4-((N-tert-butoxycarbonylaminomethyl) phenyl] propanoyl] -1-N-methylamino] ethyl] -1-2-benzo [b] thiophencarpoxa Synthesis of mid
工程 1で得られた化合物 （57. Omg) および工程 3で得られた化合物 (54. Img) を用いて、 実施例化合物 2の合成の工程 3と同様の方法で反応 を行い、 標記化合物 （22. 9mg、 実施例化合物中間体番号 6— 4) を 得た。  Using the compound (57.Omg) obtained in Step 1 and the compound (54.Img) obtained in Step 3, a reaction was carried out in the same manner as in Step 3 of the synthesis of Example Compound 2, and the title compound ( 22.9 mg, Example compound intermediate No. 6-4) was obtained.
く工程 5 > N— [2- [N— [3— [4- (アミノメチル） フエニル] プロ パノィル] 一 N—メチルァミノ] ェチル] 一 2—べンゾ [b] チォフェンカルボ キサミド塩酸塩の合成  Step 5> Synthesis of N— [2- [N— [3 -— [4- (aminomethyl) phenyl] propanoyl] -1-N-methylamino] ethyl] -12-benzo [b] thiophenecarboxamide hydrochloride
工程 4で得られた化合物 （22. 5mg) 用いて、 実施例化合物 2の合成のェ 程 4と同様の方法で反応を行い、 標記化合物 （7. 2mg) を得た。  The compound (22.5 mg) obtained in Step 4 was reacted in the same manner as in Step 4 of the synthesis of Example Compound 2 to give the title compound (7.2 mg).
(実施例化合物 7の合成）  (Synthesis of Example Compound 7)
N— ( 4 -ピペラジニルフエニル) 一 [ 1— (4一フエニル) ベンゼンスルホ 二ルー 4ーピペリジン] カルポキサミドトリフルォロ酢酸塩の合成  Synthesis of N- (4-piperazinylphenyl) -1- [1- (4-phenyl) benzenesulfo-2-ru 4-piperidine] carpoxamide trifluoroacetate
<工程 1> N— [4一 （1一 t e r t—ブトキシカルポ二ルビペラジン一 4 一ィル） フエニル] 一 (1一ベンジル一 4ーピペリジン) カルポキサミドの合成 N—べンジルイソ二ペコチン酸リチウム塩 （ 10. 0 g) の塩化メチレン ZN， N—ジメチルホルムアミド （113mLZ68mL) 懸濁液に 1 M塩化水 素—エーテル溶液 （44. 4mL) 、 1ーェチルー 3— （3—ジメチルアミノブ 口ピル） カルポジイミド塩酸塩 （8. 51 g) および 1一 t e r t—ブトキシカ ルポ二ルー 4一 （4ーァミノフエニル） ピぺラジン （11. 3g) を加え、 室温 03009738 <Step 1> Synthesis of N— [4- (1-1-tert-butoxycarbodirubiperazine-14-yl) phenyl] -1- (1-benzyl-1-piperidine) carpoxamide Lithium N-benzyl isodipecotate (10.0) g) in methylene chloride ZN, N-dimethylformamide (113mLZ68mL) suspension, 1M hydrogen chloride-ether solution (44.4mL), 1-ethyl-3- (3-dimethylaminobutyryl) carbodiimide hydrochloride (8 Add 51 g) and 1-tert-butoxycarbonyl 2- (4-aminophenyl) piperazine (11.3 g) and add room temperature. 03009738
91 で一夜攪拌した。 反応液を減圧下溶媒を留去した。 得られた残渣に水を加え、 酢 酸ェチルで抽出した。 水および飽和食塩水で洗浄、 無水硫酸ナトリウムで 乾燥後、 減圧下溶媒を留去した。 得られた残渣をシリカゲルカラムクロマト グラフィ一 （溶出溶媒；酢酸ェチル〜メタノール：塩化メチレン =1 ： 9) で精 製することにより標記化合物 （16. 5 g、 実施例化合物中間体番号 7— 1) を 得た。  Stirred overnight at 91. The solvent was distilled off from the reaction solution under reduced pressure. Water was added to the obtained residue, and extracted with ethyl acetate. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to methanol: methylene chloride = 1: 9) to give the title compound (16.5 g, intermediate of the working example compound No. 7-1) Was obtained.
<工程 2> N— [4- (1— t e r t—ブトキシカルポ二ルビペラジン一 4 一ィル） フエニル] 一 4ーピペリジンカルポキサミドの合成  <Step 2> Synthesis of N- [4- (1-tert-butoxycarbonylbiperazine-1 4-yl) phenyl] -14-piperidinecarboxamide
工程 1で得られた化合物 （6. 95 g) のメタノール （140mL) 溶液 に 10%パラジウム一炭素 （0. 70 g) を加え、 水素雰囲気下室温で一夜攪拌 した。 触媒をろ過し、 ろ液を減圧下に濃縮することにより標記化合物 （ 5. 82 g、 実施例化合物中間体番号 7— 2 ) を得た。  To a solution of the compound (6.95 g) obtained in Step 1 in methanol (140 mL) was added 10% palladium-carbon (0.70 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (5.82 g, Example compound intermediate No. 7-2).
く工程 3> N— [4一 （1 _ t e r t—ブトキシカルボニルピペラジン一 4 一ィル） フエニル] 一 [1一 (4—フエニル) ベンゼンスルホニル— 4ーピペリ ジン] 力ルポキサミド  Step 3> N— [4- (1-tert-butoxycarbonylpiperazine-141-yl) phenyl] -1- [1- (4-phenyl) benzenesulfonyl-4-piperidine]
工程 2で得られた化合物 （0. 17 g) の塩化メチレン （lmL) 溶液に （4 一フエニル) ベンゼンスルホニルクロリド (0. 10 g) 、 およびトリェチルァ ミン （66 /L) を加えて、 室温で一夜攪拌した。 反応液に水を加え、 1規定水 酸化ナトリウム水溶液を加えてアルカリ性とし、 塩化メチレンにて抽出した。 水 および飽和食塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去 した。 得られた残渣をシリカゲルカラムクロマトグラフィー [クロマトレックス NH™； Ch r oma t 0 r e xNH™] (溶出溶媒；酢酸ェチル） で精製する 2003/009738 To a solution of the compound (0.17 g) obtained in Step 2 in methylene chloride (1 mL) was added (4-phenyl) benzenesulfonyl chloride (0.10 g) and triethylamine (66 / L), and the mixture was added at room temperature. Stirred overnight. Water was added to the reaction solution, a 1N aqueous sodium hydroxide solution was added to make the reaction solution alkaline, and the mixture was extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography [Chromatorex NH ™; Chromatox rexNH ™] (elution solvent: ethyl acetate). 2003/009738
92  92
ことにより標記化合物 （0. 2 2 g、 実施例化合物中間体番号 7— 3) を 得た。 Thereby, the title compound (0.22 g, Example compound intermediate No. 7-3) was obtained.
<工程 4> N- (4ーピペラジニルフエニル） 一[ 1— (4—フエニル） ベ ンゼンスルホ二ルー 4ーピペリジン] 力ルポキサミドトリフルォロ酢酸塩の合成 工程 3で得られた化合物 (0. 12 g) にァニソ一ル (54 D 、 次いで氷 水冷下トリフルォロ酢酸 (0. 39mL) を加え、 室温で一夜攪拌した。 反応液 にエーテルを加え、 析出した沈殿物をろ取し、 エーテルで洗浄することにより標 記化合物 （0. 10g) を得た。  <Step 4> Synthesis of N- (4-piperazinylphenyl) 1- [1- (4-phenyl) benzenesulfonyl 4-piperidine] Potassium lipoxamide trifluoroacetate Compound obtained in Step 3 (0 To 12 g) was added anisol (54 D, then 0.39 mL of trifluoroacetic acid under ice water cooling), and the mixture was stirred at room temperature overnight.Ether was added to the reaction mixture, and the precipitated precipitate was collected by filtration and washed with ether. The title compound (0.10 g) was obtained by washing.
(実施例化合物 8の合成）  (Synthesis of Example Compound 8)
N— [ 1 - (4一フエニル） ベンゼンスルホ二ルー 4ーピペリジル] 一 （4一 グァニジノベンゼン） カルボキサミドメ夕ンスルホン酸塩の合成  N— [1- (4-Phenyl) benzenesulfonyl 4-piperidyl] 1- (4-guanidinobenzene) Synthesis of carboxamide sulfonic acid salt
く工程 1 > 4 - ( t e r t一ブトキシカルボニルァミノ） 一 1一 [ (4 一フエニル) ベンゼンスルホニル] ピぺリジンの合成  Step 1> Synthesis of 4- (tert-butoxycarbonylamino) 1-11-[(4-phenyl) benzenesulfonyl] piperidine
4一 ( t e r t一ブトキシカルボニルァミノ） ピぺリジン (2. 50 g) および （4—フエニル） ベンゼンスルホニルクロリド （3. 15 g) を用いて、 実施例化合物 7の合成の工程 3と同様の方法で反応を行い、 標記化合物 （ 3. 95 g、 実施例化合物中間体番号 8— 1) を得た。  4 Using (1-tert-butoxycarbonylamino) piperidine (2.50 g) and (4-phenyl) benzenesulfonyl chloride (3.15 g) in the same manner as in Step 3 of the synthesis of Example Compound 7 The reaction was carried out according to the method to give the title compound (3.95 g, intermediate of the example compound intermediate number 8-1).
く工程 2 > 4ーァミノ一 1一 [ (4—フエニル) ベンゼンスルホニル] ピぺ リジンの合成  Step 2> Synthesis of 4-amino-1-11 [(4-phenyl) benzenesulfonyl] piperidine
工程 1で得られた化合物 （ 0. 85 g ) を用いて、 実施例化合物 1の合成のェ 程 3と同様の方法で反応を行い、 標記化合物 （0. 57 g、 実施例化合物中間体 番号 8— 2) を得た。 く工程 3〉 N— [1一 （4一フエニル） ベンゼンスルホ二ルー 4ーピベリジ ル] 一 （4—グァニジノベンゼン） 力ルポキサミドメタンスルホン酸塩の合成 工程 2で得られた化合物 （0. l l g) および 4—グァニジノ安息香酸メタン スルホン酸塩 (0. 20 g) のピリジン （4mL) 溶液に、 N, N' ージシクロ へキシルカルポジイミド （0. 16 g) を加え、 室温で一夜攪泮した。 不溶物を ろ過により取り除き、 ろ液を減圧下に濃縮した。 得られた残渣をシリカゲルカラ ムクロマトグラフィー （溶出溶媒； メタノール：塩ィ匕メチレン =9 ： 1) で精製 することにより標記化合物 （5. 5mg) を得た。 Using the compound (0.85 g) obtained in Step 1, a reaction was carried out in the same manner as in Step 3 of the synthesis of Example Compound 1, and the title compound (0.57 g, Example Compound Intermediate No. 8-2) was obtained. Step 3> Synthesis of N- [1-1 (4-phenyl) benzenesulfonyl 4-piberidyl] -1- (4-guanidinobenzene) lipoxamide methanesulfonate Compound obtained in Step 2 (0 llg) and 4-guanidinobenzoic acid methanesulfonate (0.20 g) in pyridine (4 mL) were added with N, N'-dicyclohexylcarposimide (0.16 g) and stirred at room temperature overnight. did. Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methanol: chlorosilane = 9: 1) to give the title compound (5.5 mg).
(実施例化合物 9の合成）  (Synthesis of Example Compound 9)
N— [2- [N- [3— [4一 (アミノメチル) フエニル] プロピル] ァミノ] ェチル] ― (1一クロロー 2—ナフタレン） スルホンアミドニ塩酸塩の合成 く工程 1〉N— [2- [N— [3— [4一 (N- t e r t—ブトキシカルポ二 ルァミノメチル） フエニル] プロピル] ァミノ] ェチル] トリフルォロアセトァ ミドの合成 N— [2- [N- [3 -— [4- (Aminomethyl) phenyl] propyl] amino] ethyl] — (1-Chloro-2-naphthalene) sulfonamidinihydrochloride Step 1> N— [2 -Synthesis of [N— [3 -— [4- (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] amino] ethyl] trifluoroacetamide
実施例化合物 1の合成の工程 1で得られた化合物 （ 3 · 03 g) のトルエン （ 10 OmL) 溶液に N— (2—アミノエチル） トリフルォロアセトアミド塩酸塩 (4. 43 g) 、 ピリジン （0. 93mL) を加えた。 減圧下溶媒を留去し、 得 られた残渣にトルエン （8 OmL) を加え、 さらに減圧下溶媒を留去し、 この操 作を 2回繰り返した。 得られた残渣に塩化メチレン （5 OmL) を加え、 ここに トリァセトキシ水素化ホウ素ナトリウム （4. 87 g) を加えて、 窒素雰囲気下 室温で一夜攪拌した。 反応液に水を加え、 1規定水酸化ナトリウム水溶液を加え てアル力リ性とし、 塩化メチレンにて抽出した。 水および飽和食塩水で洗浄、 無 水硫酸ナトリウムで乾燥後、 減圧下溶媒を留去した。 得られた残渣をシリカゲル カラムクロマトグラフィー （溶出溶媒；塩ィ匕メチレン：メタノール =10 ： 1) で精製することにより標記化合物 （ 1. 86 g、 実施例化合物中間体番号 9一 1 ) を得た。 N- (2-Aminoethyl) trifluoroacetamide hydrochloride (4.43 g) and pyridine were added to a toluene (10 OmL) solution of the compound (303 g) obtained in Step 1 of the synthesis of Example Compound 1. (0.93 mL) was added. The solvent was distilled off under reduced pressure, and toluene (8 OmL) was added to the obtained residue. The solvent was further distilled off under reduced pressure, and this operation was repeated twice. Methylene chloride (5 OmL) was added to the obtained residue, and sodium triacetoxyborohydride (4.87 g) was added thereto, followed by stirring overnight at room temperature under a nitrogen atmosphere. Water was added to the reaction solution, and a 1N aqueous solution of sodium hydroxide was added to make the solution viscous, and the mixture was extracted with methylene chloride. Washed with water and saturated saline, no After drying over sodium hydrogen sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; methylene chloride: methanol: methanol = 10: 1) to give the title compound (1.86 g, Example compound intermediate number 911). .
く工程 2〉 N— [2— [N— t e r t—ブトキシカルポ二ルー N— [3— [ 4— (N- t e r t一ブトキシカルポニルアミノメチル) フエニル] プロピル] アミノ] ェチル] トリフルォロアセ卜アミドの合成  Step 2> Synthesis of N— [2 -— [N—tert—butoxycarpone] N— [3-—4- (N-tert-butoxycarponylaminomethyl) phenyl] propyl] amino] ethyl] trifluoroacetamide
工程 1で得られた化合物 （1. 86 g) の塩化メチレン （10 OmL) 溶液に 二炭酸ジー t e r t—プチル （1. 26 g) を加え、 室温で一夜攪拌した。 反応 液に水を加え、 塩化メチレンにて抽出した。 水および飽和食塩水で洗浄、 無水硫 酸ナトリウムで乾燥後、 減圧下溶媒を ¾去した。 得られた残渣をシリカゲルカラ ムクロマトグラフィー （溶出溶媒；塩化メチレン：メタノール =20 ： 1) で精 製することにより標記化合物 （ 2. 15 g、 実施例化合物中間体番号 9— 2 ) を 得た。  To a solution of the compound (1.86 g) obtained in Step 1 in methylene chloride (10 OmL) was added ditert-butyl dicarbonate (1.26 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with methylene chloride. After washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 20: 1) to give the title compound (2.15 g, intermediate of the Example compound 9-2). .
ぐ工程 3> 2_ [N— t e r t—ブトキシカルポ二ルー N— [3— [4— ( N- t e r t一ブトキシカルポニルアミノメチル） フエニル] プロピル] ァミノ ] ェチルァミンの合成  Step 3> 2_ [N—tert—Butoxycarporinol N— [3— [4— (N-tert-butoxycarponylaminomethyl) phenyl] propyl] amino] Ethylamine
工程 2で得られた化合物 （2. 15 g) を用いて、 実施例化合物 4の合成のェ 程 2と同様の方法で反応を行い、 標記化合物 （1. 78 g、 実施例化合物中間体 番号 9一 3) を得た。  Using the compound (2.15 g) obtained in Step 2, a reaction was conducted in the same manner as in Step 2 of the synthesis of Example Compound 4, and the title compound (1.78 g, Example Compound Intermediate No. 9-1 3) was obtained.
く工程 4〉 N- [2 - [N- t e r t—ブトキシカルポ二ルー N— [3— [ 4— (N— t e r t—ブトキシカルポニルアミノメチル） フエニル] プロピル] ァミノ] ェチル] 一 （1一クロ口— 2—ナフタレン） スルホンアミドの合成 工程 3で得られた化合物 （ 1 0. O mg) および （ 1—クロロー 2— ナフタレン） スルホニルクロリド （7. 7mg) を用いて、 実施例化合物 7の合 成の工程 3と同様の方法で反応を行い、 標記化合物 （13. 5mg、 実施例化合 物中間体番号 9一 4) を得た。 Step 4> N- [2- [N-tert-butoxycarbonyl N- [3- [4- (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] Synthesis of Amino] ethyl] 1- (1-chloro-2-naphthalene) sulfonamide Compound (10. O mg) obtained in Step 3 and (1-chloro-2-naphthalene) sulfonyl chloride (7.7 mg) The reaction was carried out in the same manner as in Step 3 of the synthesis of Example Compound 7 to give the title compound (13.5 mg, Example Compound Intermediate No. 914).
く工程 5 > N— [2— [N— [3— [4— (アミノメチル） フエニル] プロ ピル] ァミノ] ェチル] 一 （1一クロロー 2—ナフタレン） スルホンアミドニ塩 酸塩の合成  Step 5> Synthesis of N— [2 -— [N— [3-—4- (aminomethyl) phenyl] propyl] amino] ethyl] mono (1-1-chloro-2-naphthalene) sulfonamidini hydrochloride
工程 4で得られた化合物 （13. 5mg) を用いて、 実施例化合物 2の合成の 工程 4と同様の方法で反応を行い、 標記化合物 （10. Omg) を得た。  The compound (13.5 mg) obtained in Step 4 was reacted in the same manner as in Step 4 of the synthesis of Example Compound 2 to give the title compound (10. Omg).
(実施例化合物 10の合成）  (Synthesis of Example Compound 10)
N— [2— [N— [3- [4- (アミノメチル) フエニル] プロピル] -N- メチルァミノ] ェチル ] —2， 3—ナフタレンジ力ルポキシミドニ塩酸塩の合成 く工程 1 > N— [2— [N— [3— [4— (N- t e r t一ブトキシカルポ ニルアミノメチル） フエニル] プロピル] 一 N—メチルァミノ] ェチル] 一 2, 実施例化合物 2の合成の工程 2で得られた化合物 （50. Omg) のクロロホ ルム （5mL) 溶液に、 2, 3—ナフタレンジカルボン酸無水物 (34· Omg ) を加え、 3時間加熱還流した。 反応液を減圧下溶媒を留去し、 得られた残渣を シリカゲルカラムクロマトグラフィー （溶出溶媒；酢酸ェチル） で精製すること により標記化合物 （72. Omg、 実施例化合物中間体番号 10— 1) を得た。 く工程 2> N- [2- [N— [3— [4一 （アミノメチル） フエニル] プロ PC漏 00膽 738 N— [2— [N— [3- [4- (Aminomethyl) phenyl] propyl] -N-methylamino] ethyl] —Synthesis of 2,3-naphthalenedi-encapsulpoxymidoni hydrochloride Step 1> N— [2 — [N— [3 -— [4 -— (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] -1-N-methylamino] ethyl] 1,2 The compound obtained in Step 2 of the synthesis of Example Compound 2 (50 Omg) in chloroform (5 mL) was added with 2,3-naphthalenedicarboxylic anhydride (34 · Omg), and the mixture was refluxed for 3 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the title compound (72. Omg, Example compound intermediate No. 10-1). Obtained. Step 2> N- [2- [N— [3 -— [4- (Aminomethyl) phenyl] pro PC leak 00bun 738
96  96
ピル] 一 N—メチルァミノ] ェチル] —2, 3—ナフタレンジ力ルポキシミドニ 塩酸塩の合成 Synthesis of [pyr]-[1-N-methylamino] ethyl] —2,3-naphthalenediene lipoximidini hydrochloride
工程 2で得られた化合物 （72. Omg) 用いて、 実施例化合物 2の合成のェ 程 4と同様の方法で反応を行い、 標記化合物 （50. 2mg) を得た。  The compound (72. Omg) obtained in Step 2 was reacted in the same manner as in Step 4 of the synthesis of Example Compound 2 to give the title compound (50.2 mg).
(実施例化合物 11の合成）  (Synthesis of Example Compound 11)
[1— [4- (アミノメチル） フエニル] ピぺリジン一 4—ィル] 一 [1一 [ 4一 （アミノメチル） フエニル] ピぺリジン一 4 _ィルメチル] ェチルァミンの 合成 .  Synthesis of [1-[4-(aminomethyl) phenyl] piperidine-1-4-yl] 1-[1-[4-(Aminomethyl) phenyl] piperidine-1-4-methyl-ethylethylamine.
<工程 1 > [1一 [4— (N— t e r t—ブトキシカルボニルァミノメチル ) フエニル] ピぺリジンー4一ィル] 一 [1一 [4一 （Ν— t e r t—ブトキシ カルポニルアミノメチル） フエニル] ピぺリジン一 4一^ rルメチル] ェチル ァミンの合成  <Step 1> [1-1 [4- (N-tert-butoxycarbonylaminomethyl) phenyl] piperidin-4-yl] 1-1 [4-[(1-tert-butoxycarbonylaminomethyl) phenyl] Synthesis of [piperidine-1-41-r-methyl] ethylamine
実施例 3の工程 1で得られた化合物 (0. 10 g) およびァセトアルデヒド ( 0. 2 OmL) を用いて、 実施例 1の工程 2と同様の方法で反応を行い、 標記化 合物 （94. 2mg、 実施例中間体番号 11一 1 ) を得た。  Using the compound (0.10 g) obtained in Step 1 of Example 3 and acetoaldehyde (0.2 OmL), the reaction was carried out in the same manner as in Step 2 of Example 1 to give the title compound. (94.2 mg, Example intermediate No. 11-11) was obtained.
<工程 2〉 [ 1一 [4- (アミノメチル) フエニル] ピぺリジン一 4一^「ル ] ― [1 - [4一 （アミノメチル） フエニル] ピぺリジン— 4 Γルメチル] ェ チルァミンの合成  <Step 2> [1- [4- (Aminomethyl) phenyl] piperidine-4 ^^-]-[1- [4- (Aminomethyl) phenyl] pirididine-4- 4-methyl] ethylamine Synthesis
工程 1で得られた化合物 （90. Omg) を用いて、 実施例 1の工程 3と同様 の方法で反応を行い、 標記化合物 （42. 2mg) を得た。  Using the compound (90. Omg) obtained in Step 1, a reaction was carried out in the same manner as in Step 3 of Example 1 to obtain the title compound (42.2 mg).
(実施例化合物 12の合成）  (Synthesis of Example Compound 12)
N- [2- [N- [3— [4一 （アミノメチル） フエニル] プロピル] 一 N— メチルァミノ] ェチル] _ 5—インドールカルポキサミドニ塩酸塩の合成 く工程 1 > N— [2— [N- [3— [4— (N— t e r t—ブトキシカルボ ニルアミノメチル） フエニル] プロピル] 一 N—メチルァミノ] ェチル] 一 5— ィンドール力ルポキサミドの合成 N- [2- [N- [3 -— [4- (aminomethyl) phenyl] propyl] -1-N— Methylamino] ethyl] _ Synthesis of 5-indolecarpoxamidini hydrochloride Step 1> N— [2-—N- [3-—4- (N-tert-butoxycarbonylaminomethyl) phenyl] propyl] N-Methylamino] ethyl] -1-Synthesis of 5-indole-powered lipoxamide
実施例 2の工程 2で得られた化合物 （50. Omg) およびインドールー 5— カルボン酸 （30. lmg) を用いて、 実施例 2の工程 3と同様の方法で反応を 行い、 標記化合物 （50. lmg、 実施例中間体番号 12— 1) を得た。  Using the compound (50.Omg) obtained in Step 2 of Example 2 and indole-5-carboxylic acid (30.lmg), the reaction was carried out in the same manner as in Step 3 of Example 2 to give the title compound (50 lmg, Example Intermediate No. 12-1) was obtained.
く工程 2 > N— [2— [N— [3- [4- (アミノメチル） フエニル] プロ ピル] 一 N—メチルァミノ] ェチル] 一 5—インド一ルカルポキサミドニ塩酸塩 の合成  Step 2> Synthesis of N— [2 -— [N— [3- [4- (aminomethyl) phenyl] propyl] -1-N-methylamino] ethyl] -15-indolecarpoxamidoni hydrochloride
工程 1で得られた化合物 （50. lmg) を用いて、 実施例 2の工程 4と同様 の方法で反応を行い、 標記化合物 （26. 3mg) を得た。  Using the compound (50. lmg) obtained in Step 1, the reaction was carried out in the same manner as in Step 4 of Example 2, to obtain the title compound (26.3 mg).
実施例化合物 1の合成から実施例化合物 12の合成で得られた本発明の化合物 の1 H— NMRデータを表 13に、 実施例化合物の中間体の — NMRデ一夕 を表 14に示した。 Table 13 shows 1 H-NMR data of the compound of the present invention obtained from the synthesis of Example Compound 1 to the synthesis of Example Compound 12, and Table 14 shows the —NMR data of intermediates of the Example compound. .
なお、 実施例および表 14において、 例えば、 「実施例化合物中間体番号 1一 1」 とあるのは、 「実施例化合物 1の合成の工程 1」 により得られる中間体を意 味する。  In the Examples and Table 14, for example, “Example compound intermediate No. 11” means an intermediate obtained by “Step 1 of synthesis of Example compound 1”.
実施例 9 候補化合物のトリプ夕ーゼ阻害活性測定 Example 9 Measurement of Trypasease Inhibitory Activity of Candidate Compounds
トリプターゼ活性測定は実施例 3に記載の方法で行つた。 B A B I Mの代わり に実施例 8で合成した化合物を 0. 0 0 l u gZm 1〜： L 0 g/m 1を 3倍公 比で加えた。 実施例化合物 10のヒト βトリプ夕一ゼに対する阻害活性 I C5。は 0 . 0 9 9 であった。 また、 実施例化合物 1〜9、 1 1及び 1 2のヒト 3ト リプターゼに対する阻害活性 I C 5。はすべて 1 0 /x M以下であった。 産業上の利用可能性 The measurement of tryptase activity was performed by the method described in Example 3. Instead of BABIM, the compound synthesized in Example 8 was added at 0.03 lugZm1-: L0 g / m1 at a three-fold common ratio. Inhibition against human β trypsinogen evening one peptidase example compounds 10 activity IC 5. Is 0.09. Further, example compounds 1-9, inhibitory activity IC 5 against 1 1 and 1 2 of the human 3 Ta Riputaze. Were all less than 10 / xM. Industrial applicability
本発明は、 活性を持ちしかも糖鎖が切断されたトリプタ一ゼの結晶、 またはこ のトリプ夕ーゼとァフィニティを有する物質との複合体結晶を容易に得ることが できるので、 これらの結晶を使えば、 トリプターゼ阻害活性を有する化合物の化 合物アレイ、 ライブラリ一またはフアルマコフォアが、 容易に得られる。 また、 これらを用いてトリプ夕一ゼ阻害活性を有する化合物の、 スクリーニングまたは ドラッグデザィンができるので候補化合物を適切に得ることができる。 The present invention makes it possible to easily obtain tryptase crystals having an active and cleaved sugar chain, or complex crystals of this trypase and a substance having affinity. If used, compound arrays, libraries or pharmacophore of compounds having tryptase inhibitory activity can be easily obtained. In addition, screening or drug design of compounds having trypticase inhibitory activity can be carried out using these, so that candidate compounds can be appropriately obtained.
表 13(その 1) Table 13 (Part 1)
Figure imgf000100_0001
表 13(その 2)
Figure imgf000100_0001
Table 13 (Part 2)
Figure imgf000101_0001
Figure imgf000101_0001
表 14(その 1) Table 14 (Part 1)
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Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000103_0001
(½) (½)
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3 9E'2l 00 ,1 0S0"8 Zl£'6l HQ'L 6S V IVA W01V3 9E'2l 00, 1 0S0 "8 Zl £ '6l HQ'L 6S V IVA W01V
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N 29 '91 00 869 "9 999-91 ZL6'9 69 V 1VA N £92 隱 VN 29 '91 00 869 "9 999-91 ZL6'9 69 V 1VA N £ 92 Oki V
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S 90^2 00 Ί 906*1 890 "81 £68 Ί 8S V SA3 OS 09ε WOiVS 90 ^ 2 00 Ί 906 * 1 890 "81 £ 68 Ί 8S V SA3 OS 09ε WOiV
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3 6^-02 OO'L Z19'9 0 9·0 - 86 V ΝΠ3 3 601 W01V3 6 ^ -02 OO'L Z19'9 0 9-0-86 V ΝΠ3 3 601 W01V
N ιε·9ΐ OO'l 89 - Zii 'L SZ8^ 86 V N1D 2ョ N 80Z W01VN ιε9ΐ OO'l 89-Zii 'L SZ8 ^ 86 V N1D 2 ョ N 80Z W01V
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3 00" I £ 6·1- 682*9 186 ·£ 86 V N13 ao 90 鼠 V3 00 "I £ 61-682 * 9 186 · £ 86 V N13 ao 90 Rat V
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C.600/COOZdf/X3d 0 £9 "62 00 Ί S89'8L- £80'8L £9971 181 V 3UV 0 隱 VC.600 / COOZdf / X3d 0 £ 9 "62 00 Ί S89'8L- £ 80'8L £ 9971 181 V 3UV 0 Hidden V
0 8i"0£ 00 •I 9 81- ' 11 L21 ν oav 3 i W01V0 8i "0 £ 00 • I 9 81- '11 L21 ν oav 3 i W01V
N 00 ■I 868'S2- 889't^L 8Z2'2L 121 ν oy 2HN ΐ ι 隠 VN 00 ■ I 868'S2- 889't ^ L 8Z2'2L 121 ν oy 2HN ΐ ι Hidden V
N 60 "9^ 00 ■I 9C6"9Z- 9LL '9ί 280 · V 9HV LHN i 隱 VN 60 "9 ^ 00 ■ I 9C6" 9Z-9LL '9ί 280 · V 9HV LHN i Oki V
0 90 00 ■I εε 'si 680 I LSI V ZD i W01V0 90 00 ■ I εε 'si 680 I LSI V ZD i W01V
N ZVVJ 00 •I m'zz- t^08" L ·21 V DdV 3N W01VN ZVVJ 00Im'zz-t ^ 08 "L21 V DdV 3N W01V
0 z i^ 00 •I i 'εζ - οεζ*9ΐ οε -ει Ζ81 V DHV ao 隠 V0 z i ^ 00 • I i 'εζ-οεζ * 9ΐ οε -ει Ζ81 V DHV ao Hidden V
3 0 00 ■I ΙΙΙ Ι- W91 Z09"£L 121 v Dyv W01V d Ή 00 •I ην ι- ZZ9'9L E9L '21 Ζ81 mi 匪 V3 0 00 ■ I ΙΙΙ Ι- W91 Z09 "£ L 121 v Dyv W01V d Ή 00 • I ην ι- ZZ9'9L E9L '21 Ζ81 mi 81
3 9£ S 00 £81 '61- 9iO'9L ZLO'21 Ζ81 v oav vo 隱 V3 9 £ S 00 £ 81 '61-9iO'9L ZLO'21 Ζ81 v oav vo Oki V
N 00 Ί Li'6L- t-£0"9l £66'0L Ζ81 v Dy N 9£f L I/IIOIVN 00 Ί Li'6L- t- £ 0 "9l £ 66'0L Ζ81 v Dy N 9 £ f L I / IIOIV
0 0Γ61 00 ,1 62 ^ l'll 28£ '0 V v，v 0 8 i 瞧 V0 0Γ61 00, 1 62 ^ l'll 28 £ '0 V v, v 0 8 i 瞧 V
3 90"6l 00 Ί L99 "9 689 Ί2 28に 0 V V1V 0 ifl 隱 V3 90 "6l 00 Ί L99" 9 689 Ί2 28 0 V V1V 0 ifl Oki V
0 20 '02 00 ,1 ΙΕΙ ·9 299'6l 69£"l V V1V 90 W01V0 20 '02 00, 1 ΙΕΙ9 299'6l 69 £ "l V V1V 90 W01V
0 29 00 Ί ε " III ·02 £60 Ό fOL V V1V vo 隠 V0 29 00 Ί ε "III · 02 £ 60 Ό fOL V V1V vo Hidden V
N 86'6l 00 ■I 9·61 92L Ό- 01 V V1V N W01VN 86'6l 00 I 961 92L Ό-01 V V1V N W01V
0 2l'ZZ 00 'I 656· 982 "Zl επ ·1 - εοι V 311 0 隠 V0 2l'ZZ 00 'I 656982 "Zl επ1-εοι V 311 0 Hidden V
3 ΙΕΌΖ 00' 'I 6L0' 9it^'8L Ιΐί'Ο- εοι V 311 3 Z L INOiV3 ΙΕΌΖ 00 '' I 6L0 '9it ^' 8L Ιΐί'Ο- εοι V 311 3 Z L INOiV
3 ^z 00' ■L 198Ό 809 'QZ m 'ε- εοι V 311 ιαο I L 隱 V3 ^ z 00 '■ L 198Ό 809' QZ m 'ε- εοι V 311 ιαο I L Oki V
3 91*92 00' Ί εεη OLO'02 202·2- εοι V 311 133 Q L 隱 V d 02· 00 Ί 9£l "81 ίΟ 'ΐ- E0L V 311 2D3 6EZ 隠 V3 91 * 92 00 'Ί εεη OLO'02 2022- εοι V 311 133 Q L hidden V d 02
3 0£'Z2 00 Ί 2Ζ6Ί L09'8l εοι V 3 1 93 8£Z WO丄 V3 0 £ 'Z2 00 Ί 2Ζ6Ί L09'8l εοι V 3 1 93 8 £ Z WO 丄 V
3 82*02 00' Ί 82 '2 00·81 106·0- £01 V 311 V3 ζεζ 匪 V3 82 * 02 00 'Ί 82' 2 00 ・ 81 106 ・ 0- £ 01 V 311 V3 ζεζ Marauder V
N 96.91 00 'I m'i ZS9'9L frL8'0- εοι V 311 N W01VN 96.91 00 'I m'i ZS9'9L frL8'0- εοι V 311 N W01V
0 ZL'Pl 00' I 9 9'9L ιη·ο 201 V dSV O S£Z 隱 V0 ZL'Pl 00 'I 9 9'9L ιη ・ ο 201 V dSV O S £ Z Oki V
3 'l 00' Ί 6o i 686*91 962 ·0 - 201 V dSV 3 Πί IN01V3 'l 00' Ί 6o i 686 * 91 9620-201 V dSV 3 Πί IN01V
0 6Z"ll 00' Ί 6£2'0- eoo^i οιο. ε ZQI V dSV 300 εεζ 隱 V0 6Z "ll 00 'Ί 6 £ 2'0- eoo ^ i οιο.ε ZQI V dSV 300 εεζ Oki V
0 00' Ί £8 'l 69^L 201 V dSV ιαο W01V0 00 'Ί £ 8' l 69 ^ L 201 V dSV ιαο W01V
3 S0"9l 00 Ί 0^9 "0 291 201 V dSV DO ιε 隱 V3 S0 "9l 00 Ί 0 ^ 9" 0 291 201 V dSV DO ιε Hidden V
0 6に I 00' 'L 662 "0 969"0 201 V dSV ao οει W01V0 6 to I 00 '' L 662 "0 969" 0 201 V dSV ao οει W01V
3 9·91 00' Ί 6S2O- 20L V dSV o 6 隱 V3 991 00 'Ί 6S2O- 20L V dSV o 6 Hidden V
N £9 L 00' Ί nv\ t-L6"£L 969"1- 201 V dSV N UL W01VN £ 9 L 00 'Ί nv \ t-L6 "£ L 969" 1- 201 V dSV N UL W01V
0 9S"8l 00' Ί 062 '£ 802 - L0L V V1V 0 III 隱 V 0 9S "8l 00 'Ί 062' £ 802-L0L V V1V 0 III Oki V
80 T80 T
C.600/COOZdf/X3d 請 OOZ OAV 3 16'12 00 -L l ト 12に SI 9 t7'H 26 L V N"I3 ,V3 8 瞧 VC.600 / COOZdf / X3d contract OOZ OAV 3 16'12 00 -L l SI 12 t 9'H 26 LVN "I3, V3 8 瞧 V
N £6 2 00 •I 290 ·9- 090'9l ΑΠ 'SL 261 V ΝΊ3 N W01VN £ 6 200 • I 2909-090'9l ΑΠ 'SL 261 V ΝΊ3 N W01V
0 00 ■I 0^0 '9- 696'9L 0^6*11 1.61 V SA3 0 HOIV0 00 ■ I 0 ^ 0 '9- 696'9L 0 ^ 6 * 11 1.61 V SA3 0 HOIV
3 00 'I 8 9·9- i66"9L LOf '21 L6L V SAO 0 INOIV3 00 'I 8 9 9-i66 "9L LOf '21 L6L V SAO 0 INOIV
S L9'£2 00' 'I 996 "8- 99£'fl L6L V SAO 3S N01VS L9 '£ 2 00' 'I 996 "8-99 £' fl L6L V SAO 3S N01V
3 SQ'ZZ 00' 'I 606 '8- Zi8'Sl L6L V SA3 93 WOiV3 SQ'ZZ 00 '' I 606 '8- Zi8'Sl L6L V SA3 93 WOiV
3 £8 "22 00 Ί 9£l '8 - 628 "SI 161 V SAO V3 ZLPl 隱 V3 £ 8 "22 00 Ί 9 £ l '8-628" SI 161 V SAO V3 ZLPl Oki V
N VL '11 00 'I 129 "8- 968.91 161 V S N ιι ι WOIVN VL '11 00 'I 129 "8- 968.91 161 V S N ιι ι WOIV
0 wn 00' Ί Z 'Ql- 269 'SI 6zroi 061 V yョ s 0 QL l W01V0 wn 00 'Ί Z' Ql- 269 'SI 6zroi 061 V y s 0 QL l W01V
3 06 ΊΙ 00' 'I 999'6- 069"9l 061 V yョ s 3 69t-L 隱 V3 06 ΊΙ 00 '' I 999'6- 069 "9l 061 V y s 3 69t-L Oki V
0 61 1 00' l 060 "6- £LZ'9l ill'l 061 V H3S DO 89 隱 V0 61 1 00 'l 060 "6- £ LZ'9l ill'l 061 V H3S DO 89 Oki V
3 9に 00' Ί 10Γ6- 6^6 1 W8 061 V Mョ S 83 丄 9 WOIV3 9 to 00 'Ί 10Γ6- 6 ^ 6 1 W8 061 V M S 83 丄 9 WOIV
0 IVll 00' I 6 '01 - t^98"ll 199 '6 061 V >Jョ s V3 99 HOIV0 IVll 00 'I 6 '01-t ^ 98 "ll 199' 6 061 V> Jo s V3 99 HOIV
N 00' 'I 6^ 1 8LL '6 06L V i)3S N S9 隱 VN 00 '' I 6 ^ 1 8LL '6 06L V i) 3S N S9 Oki V
0 L 'n 00 "L 809 "81 £18"01 681 V dSV 0 9 1N01V0 L 'n 00 "L 809" 81 £ 18 "01 681 V dSV 0 9 1N01V
3 92 '92 00' l '6 68L V dSV 3 mi WOIV3 92 '92 00 'l' 6 68L V dSV 3 mi WOIV
0 00' Ί ト £8i"£l 698 ·8 68L V dSV 200 WOIV0 00 'Ί to £ 8i "£ l 698 · 8 68L V dSV 200 WOIV
0 H' 00' Ί ιεε' - 9997 68L V dSV ιαο 19 WOIV0 H '00' Ί ιεε '-9997 68L V dSV ιαο 19 WOIV
3 29 "8Z 00' L 16· - 266^1 86 '8 68L V dSV DO 09 隱 V3 29 "8Z 00 'L 16--266 ^ 1 86' 8 68L V dSV DO 09 Oki V
0 00' Ί 916"£L- 691"9l 68L V dSV 90 69fl INOiV0 00 'Ί 916 "£ L-691" 9l 68L V dSV 90 69fl INOiV
0 11 Z 00' l 8'£L— 062'it 68L V dSV O 89H WOIV0 11 Z 00 'l 8' £ L— 062'it 68L V dSV O 89H WOIV
N 66'92 00' Ί £Z0"9L- £Z6"ZL 108*6 68L V dSV N i WOIVN 66'92 00 'Ί £ Z0 "9L- £ Z6" ZL 108 * 6 68L V dSV N i WOIV
0 Zi'U 00' Ί 91 91— 96Z'9l W8 881 雷 0 i WOIV0 Zi'U 00 'Ί 91 91-- 96Z'9l W8 881 Thunder 0 i WOIV
0 ΪΖΊΖ 00' Ί 9£2'9L- ISE ·6 881 V m 3 WOIV0 ΪΖΊΖ 00 'Ί 9 £ 2'9L- ISE6 881 V m 3 WOIV
H ιε·ι 00' ■I 68 2- m'zz 28 ·6 881 v zm WOIV u 80 9 00' Ί 889 '02 - S99 '1 ££6'8 881 V DdV IHN WOIV H ιε · ι 00 'I 68 2- m'zz 28 · 881 v zm WOIV u 80 9 00' Ί 889 '02-S99 '1 ££ 6'8 881 V DdV IHN WOIV
897S 00' Ί 8£Z"12- Z90"6 881 V DdV ZD Z f L IN01V 897S 00 'Ί 8 £ Z "12- Z90" 6 881 V DdV ZD Z f L IN01V
N £1 '9£ 00' Ί 0£9"IZ- 0Ζ Ό2 88L v m 3N is WOIVN £ 1 '9 £ 00' Ί 0 £ 9 "IZ- 0Ζ Ό2 88L v m 3N is WOIV
3 Ζ0'62 00' Ί £E6"6l ε·8 881 V DHV ao ost WOIV3 Ζ0'62 00 'Ί £ E6 "6l ε · 8 881 V DHV ao ost WOIV
3 9L 2 00' Ί 0 ·61- 9 '6l 8 ^6 88L V 33 mi WOIV3 9L 2 00 'Ί 061-9' 6l 8 ^ 6 88L V 33 mi WOIV
3 60 2 00' Ί 22l"8L- 丄 9に 61 9 6"8 88L V ， 83 mi WOIV3 60 2 00 'Ί 22l "8L- 丄 9 to 61 9 6" 8 88L V, 83 mi WOIV
0 S9"9Z 00' Ί l 'U - 682"8L 600'OL 88L V ， O Lm WOIV0 S9 "9Z 00 'Ί l' U-682" 8L 600'OL 88L V, O Lm WOIV
N 0972 00' Ί οεε'8ΐ- 09Z71 8 ' (U 88L V OilV N \. WOIV
Figure imgf000110_0001
N 0972 00 'Ί οεε'8ΐ- 09Z71 8' (U 88L V OilV N \. WOIV
Figure imgf000110_0001
60 X60 X
ez.60oeoo^dfx3d N 6S '81 00•I 9217 £80*91 080 V ϋョ S N 6291 隱 Vez.60oeoo ^ dfx3d N 6S '81 00 • I 9217 £ 80 * 91 080 V
0 26 '91 00 Ί 9Z6'Z- 06 ·21 6 ΙΪΖ V IVA 0 mi 隱 V0 26 '91 00 Ί 9Z6'Z- 06 21 21 6 ΙΪΖ V IVA 0 mi Oki V
0 16 1 00 •I 292 1 ΙΪΖ V IVA 3 ZZ9L 隱 V0 16 1 00 • I 292 1 ΙΪΖ V IVA 3 ZZ9L Hidden V
0 28'9l 00 εζε·9 - 6Z8-6l £61 '9 ζΙΖ V 1VA 9291 1N01V0 28'9l 00 εζε9-6Z8-6l £ 61 '9 ζΙΖ V 1VA 9291 1N01V
0 86 'SI 00 •I 1^ * - 6 21 '9 Π2 V ΐνΛ ID3 9291 隱 V0 86 'SI 00 • I 1 ^ *-6 21' 9 Π2 V ΐνΛ ID3 9291 Oki V
0 S6'Zl 00 •I ws- C£8"8l Z90"9 ΐΙΖ 1VA 93 隱 V0 S6'Zl 00 • I ws- C £ 8 "8l Z90" 9 ΐΙΖ 1VA 93 Oki V
3 00 '81 00 Ί 021 'S- 298 '81 86S' ΐΙΖ V 1VA V3 £291 隠 V3 00 '81 00 Ί 021 'S- 298 '81 86S' ΐΙΖ V 1VA V3 £ 291 Hidden V
N 9S '81 00 •I 969'f- 9Ef '61 889 ·ε Π2 V 1VA N 隠 VN 9S '81 00I 969'f-9Ef '61 889Epsilon Π2 V 1VA N Hidden V
0 00 •I 9C8"0- ΠΟΌΖ SI ·8 S6L V ϋョ S 0 SOS I 隱 V0 00 • I 9C8 "0- ΠΟΌΖ SI · 8 S6L V
0 6Z "SI 00 Ί 619Ί- ιιε·6ΐ 0Z9 S6L V 3 ZOSl 隠 V0 6Z "SI 00 Ί 619Ί- ιιε6ΐ 0Z9 S6L V 3 ZOSl Hidden V
0 Pl'Pl 00 ,1 2C8"9l 0S9'8 561 V 30 109L W01V0 Pl'Pl 00, 1 2C8 "9l 0S9'8 561 V 30 109L W01V
3 Z0'8l 00 •I 6lS'l- 91071 MS ,8 961 V i)ョ s 90 0091 隱 V3 Z0'8l 00I 6lS'l- 91071 MS, 8 961 V i) ョ s 90 0091 Oki V
0 SS "91 00 ■I - 8l2'8l 961 V V3 66 隠 V u £9 "SI 00' 'I 881 ·ε- ΖΖ9'81 88£ '6 S61 V N i 隱 V0 SS "91 00 ■ I-8l2'8l 961 V V3 66 hidden V u £ 9" SI 00 '' I 881 · ε- ΖΖ9'81 88 £ '6 S61 V N i hidden V
0 ES '91 00' 'I 282 'ε - 999 '8 61 V dSV 0 mi 隠 V0 ES '91 00 '' I 282 'ε-999' 8 61 V dSV 0 mi Hidden V
0 ZL'Li 00' Ί 618'S- 262 '61 Ρ9Ρ'6 61 V dSV D 96 隱 V0 ZL'Li 00 'Ί 618'S- 262 '61 Ρ9Ρ'6 61 V dSV D 96 Oki V
0 92 '21 00' l 9Ζ6*Ζ- 899 "61 Sl6'll 61 V dSV 200 S6 W01V0 92 '21 00 'l 9Ζ6 * Ζ- 899 "61 Sl6'll 61 V dSV 200 S6 W01V
0 ζε·9ΐ 00' Ί ε02·9 - ΖΙΡΊΖ 81に 21 61 V dSV ιαο mi W01V0 ζε9ΐ 00 'Ί ε029-ΖΙΡΊΖ81 21 61 V dSV ιαο mi W01V
0 00' Ί 696*9- 'oz πι V dSV DO i 隱 V0 00 'Ί 696 * 9-' oz πι V dSV DO i Oki V
3 09·ει 00' l 001 ·9- 616'61 . εε οι πι V dSV ao 隠 V3 09 · ει 00 'l 001 · 9- 616'61 .εε οι πι V dSV ao Hidden V
3 06 1 00' Ί 209·ト πι V dSV 3 16 瞧 V3 06 1 00 'Ί 209 · πι V dSV 3 16 瞧 V
N 1^ 1 00' I 221 ·6ΐ 68ΖΊΙ 61 V dSV N 06 I 隠 VN 1 ^ 100 'I 2216 · 68ΐ 61 V dSV N 06 I Hidden V
0 £8'2l 00' l 0897- 869 "02 6 9 I £61 V AID 0 68 W01V0 £ 8'2l 00 'l 0897- 869 "02 6 9 I £ 61 V AID 0 68 W01V
3 Z9'6l 00' l ZZZ'i- 98 ·61 IS9'21 £61 V 人つ 3 3 88 隱 V3 Z9'6l 00 'l ZZZ'i- 9861 IS9'21 £ 61 V people 3 3 88 Oki V
3 Ol'QZ 00" L 81 I89'£l 961 V AID V3 mi 1N01V3 Ol'QZ 00 "L 81 I89 '£ l 961 V AID V3 mi 1N01V
N 92 "61 00' I ΡΖΖ' - Ζ6071 ιζε'ει £61 V ΑΊ3 N mi 隠 VN 92 "61 00 'I ΡΖΖ'-Ζ6071 ιζε'ει £ 61 V ΑΊ3 N mi Hidden V
0 81 ΊΖ 00· I 9 6 9ΖΙ 71 692 "fl 261 V N，3 0 mi 隠 V0 81 ΊΖ 00 · I 9 6 9 ΖΙ 71 692 "fl 261 V N, 30 mi Hidden V
3 LfZZ 00' L LZ^- 0^ *91 016'Π Ζ61 V ΝΊ3 3 i 隠 V3 LfZZ 00 'L LZ ^-0 ^ * 91 016'Π Ζ61 V ΝΊ3 3 i Hidden V
N 00' I S£8 - 909 "01 093-Π 261 V Hi Z3N 隠 VN 00 'I S £ 8-909 "01 093-Π 261 V Hi Z3N Hidden V
0 εに ιε 00' I 661 -9- 261 V N1D 130 隱 V0 ε to ιε 00 'I 661 -9- 261 V N1D 130 Hidden V
3 '92 00· I 080 'S - Ε68ΊΙ 261 V Νつ 3 ao mi W01V3 '92 00I 080 'S-Ε68ΊΙ 261 V 33 ao mi W01V
0 00' I 268 ·ε - 261 V Ν，3 DO W01V0 00 'I 268 · ε-261 V Ν, 3 DO W01V
3 18"02 00' I ΠΖ'Ρ- 9· 261 V N13 90 62W 隠 V 3 18 "02 00 'I ΠΖ'Ρ- 9261 V N13 90 62W Hidden V
(90) ）ん攀 C.600/COOZdf/X3d raj:爾 οοε ΟΛΧ N f "82 00 Ί 862 "6- 091 ·8 612 V 人 Ί3 N 299L 隠 V 0 S8"0£ 00 "L 92ΠΙ- 2987 Z09'6 l\l v nio 0 1991 隱 V 0 ε^'οε oo "t 201 '01- £U LIZ V mo 3 099L H01V 0 Z2"S£ 00" I 6Z8'6- £01 - V niD 230 6991 H01V 0 Z9 "9£ 00" I 900 " I L- Ο'ε 97 LIZ v mo 130 8991 H01V 3 017£ 00' I 921 '01- Ζ88·9 nz V mo ao Z991 H01V 3 9i "εε oo- 1 12Γ6- 9丄 9' LS LiZ V ΠΊΟ 33 999L 隠 V 3 89 "0£ 00 Ί £02'0L- 8 6 LIZ V ΠΊ3 93 9991 隠 V 3 S2'ie 00 60f '6- S107 9 ·8 nz V O W01V N ·82 00 Ί l 2·6- 8f6 LZi'L LiZ V HID N £991 隱 V 0 19ΊΕ 00 Ί SLZ'L- 8Z9"8 92Γ8 912 V AID 0 WOiV 3 £2"62 00 "L 0ΖΓ8- 9 ·8 912 V 人 Ί3 0 L991 隱 V 3 91'9Z 00 Ί UQ- - 189 "6 £11 '9 912 V 人， 3 V3 0991 隠 V N OZ^Z 00 Ί l 9 - 6£2'0L 8L0'9 912 V λΊ3 N 6 91 ΗΟΙΫ 0 99'92 00' I 9Lfr'Z- 08171 0 0"9 912 V da丄 0 8 I IN01V 0 60 00" I 223-9- SOS'S S12 V da丄 0 Zf9l 隱 V 0 88'9L 00" I 189-9- 299'9 912 V dil丄 ZHd 9t^9l 隠 V 0 00 Ί 66S '9 - £99"£ 91Z V da丄 εζο 9^9 L H01V 3 60'9L 00 "L fr9L "9- 0 ' L 912 V da丄 W01V N 20·εΐ 00" I 9L0"9- 068 '6 90 '1 912 V da丄 13N IN01V 3 06 "SL 00" I £09*f- ZOi'OL Z8£"Z 9LZ V dM Lao 91 隱 V 0 88 "LL 00· I Z8i'9- Ln'L £22' 912 V da丄 L 91 IN01V 0 6' 00 "L L£9'9- £9Z'8 066 Ί 912 V da丄 230 om 隱 V 3 zrsi 00*1 9srs- L88'8 98S ·ε 9L2 V ZQd 6£9l HOiV 3 19'Sl 00" I LZ9^- ε 01 8l9'£ 912 V da丄 3D 8E91 隱 V 0 00' I 922 ' 912 V da丄 90 E9L WO丄 V 3 ί ΊΖ 00' I 890*9- £Ζ8·11 9^*9 912 V O 9£9l 隱 V N 68.L2 00 "L 0£8"^- 090·ει 999 912 V N 9£9L W01V 0 00*1 29 ' SI ZL9"9 Z V Mョ s 0 謝 V 3 09'LZ OO'l Ιί'ΐ- 691 "El £18· IZ V ¾I3S 3 ££91 HOiV 0 9ε·εζ OO'L 9£S - 6£9"£l ιινι IZ V aョ s 30 zm 隱 V 3 '2〖 OO'l 8ES*e- 91S 1 VIZ V is ao 隠 V 3 Z9"02 OO'l 916'ε PiZ V d3S V3 0£9l 隠 V (90)) Climbing C.600 / COOZdf / X3d raj: οοε ΟΛΧ N f "82 00 Ί 862" 6-091 · 8 612 V person Ί3 N 299L hidden V 0 S8 "0 £ 00" L 92ΠΙ- 2987 Z09'6 l \ lv nio 0 1991 hidden V 0 ε ^ 'οε oo " t 201 '01-£ U LIZ V mo 3 099L H01V 0 Z2 "S £ 00" I 6Z8'6- £ 01-V niD 230 6991 H01V 0 Z9 "9 £ 00" I 900 "I L- Ο'ε 97 LIZ v mo 130 8991 H01V 3 017 £ 00 'I 921 '01-Ζ889 nz V mo ao Z991 H01V 3 9i "εε oo- 1 12Γ6- 9 丄 9' LS LiZ V ΠΊΟ 33 999L Hidden V 3 89" 0 £ 00 Ί £ 02'0L- 8 6 LIZ V ΠΊ3 93 9991 Hidden V 3 S2'ie 00 60f '6- S107 9.8 nz VO W01V N · 82 00 Ί l 2.6-6f6 LZi'L LiZ V HID N £ 991 hidden V 0 19ΊΕ 00 Ί SLZ'L- 8Z9 "8 92Γ8 912 V AID 0 WOiV 3 £ 2" 62 00 "L 0ΖΓ8- 9 · 8 912 V people Ί3 0 L991 hidden V 3 91'9Z 00 Ί UQ --189 "6 £ 11 '9 912 V people, 3 V3 0991 hidden VN OZ ^ Z 00 Ί l 9-6 £ 2'0L 8L0'9 912 V λΊ3 N 691 ΗΟΙΫ 0 99'92 00' I 9Lfr ' Z- 08171 0 0 "9 912 V da 丄 0 8 I IN01V 0 60 00" I 223-9- SOS'S S12 V da 丄 0 Zf9l Hidden V 0 88'9L 00 "I 189-9- 299'9 912 V dil丄 ZHd 9t ^ 9l Hidden V 00 00 Ί 66S '9-£ 99 "£ 91Z V da 丄 εζο 9 ^ 9 L H01V 3 60'9L 00" L fr9L "9- 0 'L 912 V da 丄 W01V N 20εΐ 00" I 9L0 "9- 068' 6 90 '1 912 V da 丄 13N IN01V 3 06" SL 00 "I £ 09 * f- ZOi'OL Z8 £ "Z 9LZ V dM Lao 91 Oki V 0 88" LL 00I Z8i'9- Ln'L £ 22 '912 V da 丄 L 91 IN01V 0 6' 00 "LL £ 9'9- £ 9Z'8 066 Ί 912 V da 丄 230 om Oki V 3 zrsi 00 * 1 9srs- L88'8 98S ・ ε 9L2 V ZQd 6 £ 9l HOiV 3 19'Sl 00 "I LZ9 ^-ε 01 8l9 '£ 912 V da 丄 3D 8E91 Oki V 0 00 'I 922' 912 V da 丄 90 E9L WO 丄 V 3 ί '00' I 890 * 9- £ Ζ8 · 11 9 ^ * 9 912 VO 9 £ 9l Oki VN 68.L2 00 "L 0 £ 8 "^-090 · ει 999 912 VN 9 £ 9L W01V 0 00 * 1 29 'SI ZL9" 9 ZVM s 0 X V3 09'LZ OO'l Ιί'ΐ- 691 "El £ 18 · IZ V ¾I3S 3 ££ 91 HOiV 0 9ε ・ εζ OO'L 9 £ S-6 £ 9 "£ l ιινι IZ V ao s 30 zm Oki V 3 '2 〖OO'l 8ES * e- 91S 1 VIZ V is ao Hidden V 3 Z9 "02 OO'l 916'ε PiZ V d3S V3 0 £ 9l Hidden V
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0 01 'S2 00 .1 m's 9S8 1 LZ9'PP 6LZ g A13 0 2Z9£ 隱 V0 01 'S2 00 .1 m's 9S8 1 LZ9'PP 6LZ g A13 0 2Z9 £ Oki V
0 ΙΖ'Π 00 'I 8 ' 6 96071 W£ 61Z a 人" 13 3 LZ9£ W01V0 ΙΖ'Π 00 'I 8' 6 96071 W £ 61Z a person "13 3 LZ9 £ W01V
3 S8'L2 00' l 6^*6 SIZ g人 Ί3 V3 0Z9£ W01V3 S8'L2 00 'l 6 ^ * 6 SIZ g people Ί3 V3 0Z9 £ W01V
N 06 'ΖΖ 00' Ί L60'6 PI '9L 6 0· 612 g λΊ3 N 699£ W01VN 06 'ΖΖ 00' Ί L60'6 PI '9L 6 0 ・ 612 g λΊ3 N 699 £ W01V
0 OS' 00' Ί 221 ΊΙ SS9'9l lS6"9f LiZ g mo 0 89S£ 隱 V0 OS '00' Ί 221 ΊΙ SS9'9l lS6 "9f LiZ g mo 0 89S £ Oki V
3 86·ε2 00' l 096 '6 9^1 '91 690 "9^ LIZ 9 mo 3 i IN01V3 86ε2 00 'l 096' 6 9 ^ 1 '91 690 "9 ^ LIZ 9 mo 3 i IN01V
0 10'9£ 00' Ί 28 ' 01 298*11 S81 "19 LIZ 9 330 999£ 隱 V0 10'9 £ 00 'Ί 28' 01 298 * 11 S81 "19 LIZ 9 330 999 £ Oki V
0 u ·2ε 00' L 69'U ε'6 LiZ 8 nio L30 999£ 隱 V0 u2ε 00 'L 69'U ε'6 LiZ 8 nio L30 999 £ Hidden V
3 12·9ε 00' l ziroi 010 1 9S6.6 LIZ a nio GO z W01V3 129ε 00 'l ziroi 010 1 9S6.6 LIZ a nio GO z W01V
3 ii 'ΐε 00' l 9SI"6 m'zi ·6 m 9 nio D3 W01V3 ii 'ΐε 00' l 9SI "6 m'zi6 m9 nio D3 W01V
3 00' Ί ε ·οι 191 ' Ρ nz 9 ΠΊ3 83 39S9 隱 V3 00 'Ί ε · οι 191' Ρ nz 9 ΠΊ3 83 39S9 Oki V
0 96 2 00' 'L ' 6 199^1 nz a ΠΊ0 V3 L99£ 隱 V0 96 2 00 '' L '6 199 ^ 1 nz a ΠΊ0 V3 L99 £ Hidden V
N 00' l 8S0"6 9S8"9l 891 ' Ρ nz a mo N 099£ 隱 VN 00 'l 8S0 "6 9S8" 9l 891' Ρ nz a mo N 099 £ Oki V
0 00' Ί 898 "9 I8f "91 928■ 912 AID 0 6S9£ INOIV0 00 'Ί 898 "9 I8f" 91 928 ■ 912 AID 0 6S9 £ INOIV
3 ss' 00' l 9827 £Zl '91 912 9 kid 3 8S98 隠 V3 ss '00' l 9827 £ Zl '91 912 9 kid 3 8S98 Hidden V
3 00' Ί m L 680 '6^ 9 g 人 Ί3 V3 199£ 隱 V3 00 'Ί m L 680' 6 ^ 9 g person Ί3 V3 199 £ Oki V
N 8971 00' l 290 ·9 SOI ·6 912 s AID N 99S£ 隱 VN 8971 00 'l 2909 SOI6 912 s AID N 99S £ Oki V
0 80 1 00' 'L 02Γ9 t7£6"6l 9L2 a dil丄 0 S99£ WOiV0 80 1 00 '' L 02Γ9 t7 £ 6 "6l 9L2 a dil 丄 0 S99 £ WOiV
3 LI 71 00' Ί 009 'S ZS6'8l 9l£'6 912 8 dil丄 3 MS£ 隠 V3 LI 71 00 'Ί 009' S ZS6'8l 9l £ '6 912 8 dil 丄 3 MS £ concealed V
3 OL; 00' L 89"9 89"9L L26"£S 912 9 dil丄 2H3 £99C 隠 V3 OL; 00 'L 89 "9 89" 9L L26 "£ S 912 9 dil 丄 2H3 £ 99C Hidden V
3 00' l 6^-9 0£2'Sl 199 1Z g εζο 2SS£ 隱 V3 00 'l 6 ^ -9 0 £ 2'Sl 199 1Z g εζο 2SS £ Oki V
3 00' 'L 998"9 8£9"9L LZ e dill Z10 199£ 瞧 V3 00 '' L 998 "9 8 £ 9" 9L LZ e dill Z10 199 £ 瞧 V
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3 80Ί2 00' Ί £99 ,S 889 Ί9 SIS g du £33 隱 V 3 80Ί2 00 'Ί £ 99, S 889 Ί9 SIS g du £ 33 Hidden V
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C.600/COOZdf/X3d 12 表 7(その 17) C.600 / COOZdf / X3d 12 Table 7 (Part 17)
ATOM 3581 CB ALA B 221 41.954 21.237 14.581 1.00 24.71 C ATOM 3582 C ALA B 221 43.274 19.185 15.107 1.00 27.53 C ATOM 3583 0 ALA B 221 42.592 19.087 16.127 1.00 26.10 0 ATOM 3584 N GLN B 221A 44.087 18.222 14.683 1.00 26.35 N ATOM 3585 CA GLN B 221A 44.246 16.980 15.428 1.00 29.24 C ATOM 3586 CB GLN B 221A 44.574 15.836 14.465 1.00 31.77 C ATOM 3587 CG GLN B 221A 43.743 14.585 14.673 1.00 37.69 C ATOM 3588 CD GLN B 221A 42.329 14.726 14.144 1.00 37.67 C ATOM 3589 0E1 GLN B 221A 42. Ill 14.759 12.938 1.00 42.68 0 ATOM 3590 NE2 GLN B 221A 41.363 14.811 15.045 1.00 35.58 N ATOM 3591 C GLN B 221A 45.383 17.156 16.452 1.00 27.71 C ATOM 3592 0 GLN B 221A 46.337 17.892 16.211 1.00 27.91 0 HETATM 3791 固 B 301 48.054 15.410 -2.169 1.00 24.38 N HETATM 3792 C1 AN B 301 46.970 14.458 -1.932 1.00 20.80 C HETATM 3793 C2 NAN B 301 46.019 14.867 -0.797 1.00 17.76 C HETATM 3794 SI NAN B 301 49.643 14.855 -1.820 1.00 19.31 S HETATM 3795 01 NAN B 301 50.673 15.786 -2.456 1.00 26.34 0 HETATM 3796 02 画 B 301 49.897 14.868 -0.305 1.00 23.50 0 HETATM 3797 C3 NAN B 301 50.887 11.568 -5.642 1.00 15.63 C HETATM 3798 C4 NAN B 301 51.106 10.284 -6.125 1.00 16.39 C HETATM 3799 C5 NAN B 301 50.971 9.160 -5.268 1.00 16.41 C HETATM 3800 C6 画 B 301 50.615 9.323 -3.932 1.00 13.09 c HETATM 3801 C7 NAN B 301 50.383 10.625 -3.401 1.00 13.27 c HETATM 3802 C8 画 B 301 50.522 11.776 -4.274 1.00 15.43 c HETATM 3803 C9 NAN B 301 50.287 13.069 -3.741 1.00 14.72 c HETATM 3804 CIO NAN B 301 49.927 13.264 -2.407 1.00 17.45 c HETATM 3805 C11 画 B 301 49.797 12.124 -1.565 1.00 14.42 c HETATM 3806 CI 2 謹 B 301 50.018 10.842 -2.040 1.00 14.39 c HETATM 3807 C13 NAN B 301 45.124 18.995 3.854 1.00 17.93 c HETATM 3808 CI 4 NAN B 301 44.671 18.401 2.529 1.00 18.17 c HETATM 3809 CI 5 NAN B 301 45.416 18.180 4.958 1.00 19.03 c HETATM 3810 C16 NAN B 301 45.831 18.724 6.175 1.00 14.93 c HETATM 3811 C17 NAN B 301 45.973 20.099 6.353 1.00 14.50 c N 9£'6L 00 Ί 109 '8 l OS 69 3 1VA N 98Lf W01VATOM 3581 CB ALA B 221 41.954 21.237 14.581 1.00 24.71 C ATOM 3582 C ALA B 221 43.274 19.185 15.107 1.00 27.53 C ATOM 3583 0 ALA B 221 42.592 19.087 16.127 1.00 26.10 0 ATOM 3584 N GLN B 221A 44.087 18.222 14.683 1.00 26.35 N CA GLN B 221A 44.246 16.980 15.428 1.00 29.24 C ATOM 3586 CB GLN B 221A 44.574 15.836 14.465 1.00 31.77 C ATOM 3587 CG GLN B 221A 43.743 14.585 14.673 1.00 37.69 C ATOM 3588 CD GLN B 221A 42.329 14.726 14.144 OM 37. B 221A 42.Ill 14.759 12.938 1.00 42.68 0 ATOM 3590 NE2 GLN B 221A 41.363 14.811 15.045 1.00 35.58 N ATOM 3591 C GLN B 221A 45.383 17.156 16.452 1.00 27.71 C ATOM 3592 0 GLN B 221A 46.337 17.892 16.211 1.00 27.91 0HE 27.91 0 301 48.054 15.410 -2.169 1.00 24.38 N HETATM 3792 C1 AN B 301 46.970 14.458 -1.932 1.00 20.80 C HETATM 3793 C2 NAN B 301 46.019 14.867 -0.797 1.00 17.76 C HETATM 3794 SI NAN B 301 49.643 14.855 -1.820 1.00 19.31 S HETATM 3795 01 NAN B 301 50.673 15.786 -2.456 1.00 26.34 0 HETATM 3796 02 B 301 49.897 14.868 -0.305 1.00 23.50 0 HETATM 3797 C3 NAN B 301 50.887 11.568 -5.642 1.00 15.63 C HETATM 3798 C4 NAN B 301 51.106 10.284 -6.125 1.00 16.39 C HETATM 3799 C5 NAN B 301 50.971 9.160 -5.268 1.00 16.41 C HETATM 3800 C6 image B 301 50.615 9.323 -3.932 1.00 13.09 c HETATM 3801 C7 NAN B 301 50.383 10.625 -3.401 1.00 13.27 c HETATM 3802 C8 image B 301 50.522 11.776 -4.274 1.00 15.43 c HETATM 3803 C9 NAN B 301 50.287 13.069 -3.741 1.00 14.72 c HETATM 3804 CIO NAN B 301 49.927 13.264 -2.407 1.00 17.45 c HETATM 3805 C11 Drawing B 301 49.797 12.124 -1.565 1.00 14.42 c HETATM 3806 CI 2 Genuine B 301 50.018 10.842 -2.040 1.00 14.39 c HETATM 3807 C13 NAN B 301 45.124 18.995 3.854 1.00 17.93 c HETATM 3808 CI 4 NAN B 301 44.671 18.401 2.529 1.00 18.17 c HETATM 3809 CI 5 NAN B 301 45.416 18.180 4.958 1.00 19.03 c HETATM 3810 C16 NAN B 301 45.831 18.724 6.175 1.00 14.93 c HETATM 3811 C17 NAN B 301 45.973 20.099 6.353 1.00 14.50 c N 9 £ '6L 00 Ί 109' 8 l OS 69 3 1VA N 98Lf W01V
0 9L 71 00" I 16Γ8 226 '0 - 126 8S SAG 0 HI WOiV0 9L 71 00 "I 16Γ8 226 '0-126 8S SAG 0 HI WOiV
3 60'8l 00 'L 68 ' £9Γ0 - 080 ·6 8S 3 SAO 3 £81 隱 V3 60'8l 00 'L 68' £ 9Γ0-080 · 6 8S 3 SAO 3 £ 81 Oki V
S 00' I LZrt^ 998 - Ζ9Γ617 89 3 SAO DS 28L17 隠 VS 00 'I LZrt ^ 998-Ζ9Γ617 89 3 SAO DS 28L17 Hidden V
3 90 L 00· I θ·9 ιινζ- W6 9S 3 SAO ao 18 W01V3 90 L 00I θ9 ιινζ- W6 9S 3 SAO ao 18 W01V
3 9671 00 'L 66Γ9 9£6*0- S62.6 8S 3 SAO V3 08 HOiV3 9671 00 'L 66Γ9 9 £ 6 * 0- S62.6 8S 3 SAO V3 08 HOiV
N OO'U 00' I 820 '9 002*0- 8S 3 SA3 N SLIP 隱 VN OO'U 00 'I 820' 9 002 * 0- 8S 3 SA3 N SLIP Oki V
0 ZQ'Ll 00· I 928*9 ε ·ι IS 3 SIH 0 211V 隠 V0 ZQ'Ll 00I 928 * 9 ει IS 3 SIH 0 211V Hidden V
3 01 'U 00 Ί Z8Z'S 660 Ί S 'OS Ζ9 0 SIH 3 LLI 隱 V3 01 'U 00 Ί Z8Z'S 660 Ί S' OS Ζ9 0 SIH 3 LLI Oki V
N L6"9l 00· I £6Z'l 81S ·0 0 ' 6 ZS 0 SIH 23N 92 If W01VN L6 "9l 00I £ 6Z'l 81S0 0 '6 ZS 0 SIH 23N 92 If W01V
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3 81 00 Ί 8 ·5 6£i'L9 Ζ9 3 SIH V3 OLI HOIV3 81 00 Ί 8 · 5 6 £ i'L9 Ζ9 3 SIH V3 OLI HOIV
N 98' L 00 'L 8£9*9 106 "0 68879 Ζ9 3 SIH N 69 HOiVN 98 'L 00' L 8 £ 9 * 9 106 "0 68879 Ζ9 3 SIH N 69 HOiV
0 ' 61 00" I 98i'i 968 Ό 69i'29 9S 3 V1V 0 891 WOiV0 '61 00 "I 98i'i 968 Ό 69i'29 9S 3 V1V 0 891 WOiV
3 00 "L ί ΖΖ9"0 61£'£9 99 3 V1V 0 29Lfr 隱 V3 00 "L ί ΖΖ9" 0 61 £ '£ 9 99 3 V1V 0 29Lfr Oki V
3 '8L 00 Ί £88·9 8 ' 0 018*99 9S 3 V1V ao 99Lf 隱 V3 '8L 00 Ί £ 889 8' 0 018 * 99 9S 3 V1V ao 99Lf Hidden V
3 I9"6l 00Ί £08'9 96ε·0- 9S 3 V1V V3 S9lf 隱 V3 I9 "6l 00Ί £ 08'9 96ε0-9S 3 V1V V3 S9lf Hidden V
N 81 00 Ί 6^9 '9 982·1- 8 'M 99 3 V1V N fr9 隠 VN 81 00 Ί 6 ^ 9 '9 982 1-8' M 99 3 V1V N fr9 hidden V
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3 LS'OZ 00 'I 029*0 998*91 ι.οε 8 NVN ZZ z 隨丄ョ H3 LS'OZ 00 'I 029 * 0 998 * 91 ι.οε 8 NVN ZZ z
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C.600/COOrdf/X3d 3 92"9t 00Ί £28 '8 Ζ66·6 129 'SS S6 3 ιαο ost^ WOiV 0 "•81 00Ί 097 OSOOl 6 0"9S 96 0 丄 隱 V 0 61 00' I 690-6 2179 96 3 iU丄 ao 20 f W01V 3 1 '02 00 Ί U6'9 819'99 96 0 iUJL VD lO t' 隱 V N Z 'Ll OO'L IZ9"9 199-9 20979 96 3 a人丄 N 009t? 隱 V 0 IE "02 OO'l IZZ'8 εεに 9 6 6· 176 3 3Hd 0 66^ 隱 V 3 6£"0Z OO'l 9L9 ·ί Ζ96'9 ZLl'89 6 3 3Hd 3 謝 隠 V 3 8 8L OO'l 619 '9 9 2 'f 9 6 3Hd Z3 隱 V 3 S'9l OO'l 0S6'9 Ζ ί ' 6 3Hd 230 96^ 隱 V 3 Z9"6l OO'l 989 90S 'S9 f6 3Hd 133 S6^ W01V 3 ΙΓ81 OO'l ε ' 6·ε 98 '99 fr6 3Hd 203 隱 V 3 Ιΐ'ίΙ OO'L 89Γ9 908"£ f69'99 6 3Hd ιαο 隠 V 3 20'6L OO'L 9Ε9"9 W£ 9^8 '99 6 3 HHd 03 隱 V 3 9 61 OO'l S O' 989 ·£ Zf2"89 6 3 3Hd ao i IN01V 3 86Ί2 OO'l 900 ' 丄丄 8 ' 0'6S H 3 3Hd V3 W01V N 90 "£2 OO'L 9U'i OOS'09 6 3 3Hd N 68 隱 V 0 Z0' Z 00 Ί 6S9 I 8S6'S £ '£S V09 0 0¾id 0 ZOZP 謝 V 3 OO'l 999 ΊΙ 9f6"9 Z99 9 V09 0 Odd 3 10 V 3 8'12 OO'L L£0'6 ZfL V09 3 Oild 03 00 隠 V 0 i£'L2 OO'l 020'i. 19819 V09 0 Odd go 66 謝 V 0 22^2 OO'l V09 3 Odd V3 86 隱 V 3 1 'Z2 OO'L 692 '8 1789 '9 丄 60'2S V09 D OHd CD 16tf H01V N ZL'U OO'L ΜΓ6 V09 3 oad N 961 W01V 0 LS'ZZ OO'l ΟΠ '8 09 0 人， 3 0 S6 隠 V 3 n'n oo Ί ΙΖΟ'6 Ζ0 Ί5 09 0 人， 3 3 61 隠 V 3 98"£2 OO'l Ε80ΌΙ 289'IS 09 D Λ w Vつ J £61^ 隠 V N ΙΓ92 OO'L 869 ·6 LOO '2 286 Ό9 09 3 AID N Z6 WOiV 0 WU OO'l 210Ί 69 3 ，VA 0 16 H01V 0 ^'n oo'i Ζ99ΌΙ 686*0 8£8"09 69 0 "1VA 3 061 H01V 3 9Γ2Ζ OO'L 0£Z"L- 6S 3 1VA 233 681^ WOiV 3 OO'L 0 ' 01 9897- 608 "6f 69 3 "lVA L33 88 WOIV 3 ^ΊΖ OO'l LLP'l- 8Ζ9Ό9 69 0 "IVA 93 Z8 画 3 ll'll OO'L 9 O'Ol £60 OS 6S "IVA V3 98 WOiV
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CZ.600 / COOZ: df / X3d 3 63 '91 00 8 ££ '0t S09'89 66 0 311 l DO "S 隐 V
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D £1*12 00 "L 9267- 9εε·8 86 3 N13 33 LZ^ 隱 VD £ 1 * 12 00 "L 9267-9εε · 8 86 3 N13 33 LZ ^ Hidden V
0 18'81 00 •I 6 9'8 86 0 ΝΊ3 93 9Z f W01V0 18'81 00I6 9'8 86 0 ΝΊ3 93 9Z f W01V
0 08 "61 00 •I 826 "l- W 80£"9S 86 0 HID VO S2S 隱 V0 08 "61 00 • I 826" l- W 80 £ "9S 86 0 HID VO S2S Oki V
H VI '8L 00 •I 009 Ό- 09Γ9 099 "S9 86 0 N10 N W01VH VI '8L 00I009 Ό- 09 Γ9 099 "S9 86 0 N10 N W01V
0 86 1 00 Ί 96に L- 908· £0Z'99 16 3 V V 0 H01V0 86 1 00 Ί L-908 at 96 £ 0Z'99 16 3 V V 0 H01V
3 26"8L 00' Ί EZS'O- 98^-9 丄 6 3 V，V 3 W01V3 26 "8L 00 'EZ EZS'O- 98 ^ -9 丄 63 V, V 3 W01V
3 98*31 00' Ί 982*0 9 26 3 V1V ao 圆3 98 * 31 00 'Ί 982 * 0 9 26 3 V1V ao 圆
3 89 L 00' 'L 989 Ό 9Ζ8· 802*99 6 3 V1V V3 ozs 隠 V3 89 L 00 '' L 989 Ό 9Ζ8802 * 99 6 3 V1V V3 ozs Hidden V
N £に 00' Ί 888 'S 68Z"f 16 3 V1V N 61 隱N £ 00 '888 888' S 68Z "f 16 3 V1V N 61 Hidden
0 91 ·61 00' l £88'99 96 3 MH1 0 81 隠 V0 9161 00 'l £ 88'99 96 3 MH1 0 81 Hidden V
0 8Γ81 00' Ί ZZVZ 06 ·9 929 "9S 96 0 mi 3 IN01V0 8 Γ 81 00 'Ί ZZVZ 069 929 "9S 96 0 mi 3 IN01V
3 967 00' Ί 992Ί '8 80Γ99 96 3 mi EDD 9LSf 隠 V3 967 00 'Ί 992 Ί' 8 80 Γ 99 96 3 mi EDD 9LSf Hidden V
0 t^E "81 00' Ί ε90·ε Z69'6 tO6"£9 96 3 mi 130 L917 W01V0 t ^ E "81 00 'ε ε90 · ε Z69'6 tO6" £ 9 96 3 mi 130 L917 W01V
3 6Γ91 00' I £6·8 62Γ99 96 0 mi 03 画3 6Γ91 00 'I £ 6.88 62Γ99 96 0 mi 03 images
0 IVll 00' Ί Z6S'£ 9£S"Z f£l-S9 96 3 V3 ει 隠 V0 IVll 00 'Ί Z6S' £ 9 £ S "Z f £ l-S9 96 3 V3 ει Hidden V
N 00' I iS^ 9^9 9i6'99 96 3 mi N 21S W01VN 00 'I iS ^ 9 ^ 9 9i6'99 96 3 mi N 21S W01V
0 00' L 6£0"9 028 'Z 96 3 0 W01V0 00 'L 6 £ 0 "9 028' Z 96 3 0 W01V
3 £に 12 00' I 86i'S £697 98 ' SS 96 3 3 01S 隱3 £ to 12 00 'I 86i'S £ 697 98' SS 96 3 3 01S Hidden
0 00' I S9Z"8 19S I H0"E 96 3 HO 60S 陋0 00 'I S9Z "8 19S I H0" E 96 3 HO 60S
0 0272 00' L 6εε·8 ΙΙ ΊΙ 96 3 Z3 80 陋0 0272 00 'L 6εε8 ΙΙ ΊΙ 96 3 Z3 80
D 99*8L 00' I 69i-U 99f '^9 S6 0 Ui. 233 0 f W0IVD 99 * 8L 00 'I 69i-U 99f' ^ 9 S6 0 Ui. 233 0 f W0IV
0 6£'8l 00' L 029 '9 926 ΌΙ 96 0 UL 200 90S 画0 6 £ '8l 00' L 029 '9 926 ΌΙ 96 0 UL 200 90S picture
3 ， 02 00' I SW6 l£8"0l £6 ^9 S6 3 丄 L33 SOS 画 3, 02 00 'I SW6 l £ 8 "0l £ 6 ^ 9 S6 3 丄 L33 SOS picture
C.600/£OOZdf/X3d 請 ΟΟΖ ΟΛ\ 表 7(その 21) C.600 / £ OOZdf / X3d contract ΟΟΖ ΟΛ \ Table 7 (Part 21)
ATOM 4538 CD1 ILE C 99 58.355 11.018 2.925 1.00 12.82 CATOM 4538 CD1 ILE C 99 58.355 11.018 2.925 1.00 12.82 C
ATOM 4539 C ILE C 99 60.088 7.087 0.230 1.00 21.83 CATOM 4539 C ILE C 99 60.088 7.087 0.230 1.00 21.83 C
ATOM 4540 0 ILE C 99 7.079 -0.182 1.00 20.74 0ATOM 4540 0 ILE C 99 7.079 -0.182 1.00 20.74 0
ATOM 4541 N GLY C 100 59.465 5.993 0.678 1.00 18.63 NATOM 4541 N GLY C 100 59.465 5.993 0.678 1.00 18.63 N
ATOM 4542 CA GLY C 100 60.152 4.709 0.698 1.00 19.60 CATOM 4542 CA GLY C 100 60.152 4.709 0.698 1.00 19.60 C
ATOM 4543 C GLY C 100 60.088 3.919 1.00 19.94 CATOM 4543 C GLY C 100 60.088 3.919 1.00 19.94 C
ATOM 4544 0 GLY C 100 59.348 4.258 2.925 1.00 20.33 0ATOM 4544 0 GLY C 100 59.348 4.258 2.925 1.00 20.33 0
ATOM 4545 N ALA C 101 60.864 2.845 2.058 1.00 19.92 NATOM 4545 N ALA C 101 60.864 2.845 2.058 1.00 19.92 N
ATOM 4546 CA ALA C 101 60.922 1.996 3.241 1.00 20.34 CATOM 4546 CA ALA C 101 60.922 1.996 3.241 1.00 20.34 C
ATOM 4547 CB ALA C 101 61.616 2.747 4.379 1.00 21.46 CATOM 4547 CB ALA C 101 61.616 2.747 4.379 1.00 21.46 C
ATOM 4548 C ALA C 101 59.542 1.521 3.692 1.00 CATOM 4548 C ALA C 101 59.542 1.521 3.692 1.00 C
ATOM 4549 0 ALA C 101 59.237 1.498 4.892 1.00 19.35 0ATOM 4549 0 ALA C 101 59.237 1.498 4.892 1.00 19.35 0
ATOM 4550 N ASP C 102 58.706 1.130 2.735 1.00 20.14 NATOM 4550 N ASP C 102 58.706 1.130 2.735 1.00 20.14 N
ATOM 4551 CA ASP C 102 57.373 0.660 3.079 1.00 17.89 CATOM 4551 CA ASP C 102 57.373 0.660 3.079 1.00 17.89 C
ATOM 4552 CB ASP C 102 56.410 0.902 1.924 1.00 16.84 CATOM 4552 CB ASP C 102 56.410 0.902 1.924 1.00 16.84 C
ATOM 4553 CG ASP C 102 54.970 0.654 2.319 1.00 16.61 cATOM 4553 CG ASP C 102 54.970 0.654 2.319 1.00 16.61 c
ATOM 4554 0D1 ASP C 102 54.710 0.494 3.537 1.00 14.94 0ATOM 4554 0D1 ASP C 102 54.710 0.494 3.537 1.00 14.94 0
ATOM 4555 0D2 ASP C 102 54.108 0.627 1.415 1.00 14.32 0ATOM 4555 0D2 ASP C 102 54.108 0.627 1.415 1.00 14.32 0
ATOM 4556 C ASP C 102 57.416 -0.823 3.431 1.00 16.38 cATOM 4556 C ASP C 102 57.416 -0.823 3.431 1.00 16.38 c
ATOM 4557 0 ASP C 102 57.021 - 1.682 2.644 1.00 14.64 0ATOM 4557 0 ASP C 102 57.021-1.682 2.644 1.00 14.64 0
ATOM 4558 N ILE C 103 57.889 -1.116 4.636 1.00 17.01 NATOM 4558 N ILE C 103 57.889 -1.116 4.636 1.00 17.01 N
ATOM 4559 CA ILE C 103 58.020 -2.494 5.082 1.00 16.60 CATOM 4559 CA ILE C 103 58.020 -2.494 5.082 1.00 16.60 C
ATOM 4560 CB ILE C 103 59.411 -3.038 4.677 1.00 17.34 CATOM 4560 CB ILE C 103 59.411 -3.038 4.677 1.00 17.34 C
ATOM 4561 CG2 ILE C 103 60.476 -2.421 5.557 1.00 16.02 cATOM 4561 CG2 ILE C 103 60.476 -2.421 5.557 1.00 16.02 c
ATOM 4562 CGI ILE C 103 59.441 - 4.561 4.778 1.00 20.19 cATOM 4562 CGI ILE C 103 59.441-4.561 4.778 1.00 20.19 c
ATOM 4563 CD1 ILE c 103 60.623 -5.188 4.050 1.00 19.97 cATOM 4563 CD1 ILE c 103 60.623 -5.188 4.050 1.00 19.97 c
ATOM 4564 C ILE c 103 57.834 -2.618 6.597 1.00 15.51 cATOM 4564 C ILE c 103 57.834 -2.618 6.597 1.00 15.51 c
ATOM 4565 .0 ILE c 103 58.200 7.361 1.00 15.13, 0ATOM 4565 .0 ILE c 103 58.200 7.361 1.00 15.13, 0
ATOM 4566 N ALA c 104 57.259 -3.733 7.022 1.00 14.78 NATOM 4566 N ALA c 104 57.259 -3.733 7.022 1.00 14.78 N
ATOM 4567 CA ALA c 104 57.024 -3.969 8.432 1.00 14.33 cATOM 4567 CA ALA c 104 57.024 -3.969 8.432 1.00 14.33 c
ATOM 4568 CB ALA c 104 55.722 -3.303 8.867 1.00 11.93 cATOM 4568 CB ALA c 104 55.722 -3.303 8.867 1.00 11.93 c
ATOM 4569 C ALA c 104 56.970 -5.455 8.728 1.00 13.72 cATOM 4569 C ALA c 104 56.970 -5.455 8.728 1.00 13.72 c
ATOM 4570 0 ALA c 104 56.839 -6.281 7.822 1.00 14.63 0 3 LS'lZ 00•L IZl "9- S68'8 061 0 yョ S 83 WOiVATOM 4570 0 ALA c 104 56.839 -6.281 7.822 1.00 14.63 0 3 LS'lZ 00 • L IZl "9- S68'8 061 0 yo S 83 WOiV
3 68'6l 00 •I 8Z97- 961 '9- 289'^ 061 ϋョ S V3 10ES 面3 68'6l 00I8Z97- 961 '9- 289' ^ 061
N LL'iZ 00 •L 290 '6 - 80·5- SI 8 061 3 m N ooes W01¥N LL'iZ 00L 290 '6-805-SI 8 061 3 m N ooes W01 ¥
0 Wll 00 •I 8Ζ8·6- Z8S"9- 681 3 dSV 0 662S 面0 Wll 00 • I 8Ζ8-Z8S "9-681 3 dSV 0 662S plane
0 Ll'lZ 00 •I 190'OL- εζζ'9- 999 681 0 dSV 3 8629 面0 Ll'lZ 00I 190'OL- εζζ'9- 999 681 0 dSV 3 8629 surface
0 08 '92 00 •I n ni'\ - εΐ8"ΐ- £W8 681 3 dSV ZQO Z629 画0 08 '92 00 • In ni '\-εΐ8 "ΐ- £ W8 681 3 dSV ZQO Z629 picture
0 8 22 00 Ί 912"0L- LI 6 681 0 dSV ιαο 9629 面0 8 22 00 Ί 912 "0L-LI 6 681 0 dSV ιαο 9629 surface
3 00 •I t790'Ll 1- ειο·ε - 0 9'8fr 681 3 dSV 93 9629 H01V3 00I t790'Ll 1- ειο ・ ε-0 9'8fr 681 3 dSV 93 9629 H01V
3 8ΖΊ2 00 •I 0 8· 11 - 681 0 dSV 83 ^629 H01V3 8ΖΊ2 00I 0 811-681 0 dSV 83 ^ 629 H01V
0 9 Z 00 "I WIL- 06^*9- 68L 0 dSV V3 隱 V0 9 Z 00 "I WIL- 06 ^ * 9- 68L 0 dSV V3 Hidden V
N Ζ0'9Ζ 00 ■I 681 3 dSV N 262S 隱 VN Ζ0'9Ζ 00 ■ I 681 3 dSV N 262S Oki V
0 ττ'νι 00 •I 990"fl- 6Ε9 "9- SZ6'8 881 0 DiiV 0 L629 H01V0 ττ'νι 00I 990 "fl-6Ε9" 9- SZ6'8 881 0 DiiV 0 L629 H01V
3 8872 00 ■I V%\~ 20£"9- 9L0'8 88L 3 雷 0 0629 W01V3 8872 00 ■ I V% \ ~ 20 £ "9-9L0'8 88L 3 Lightning 0 0629 W01V
N 8Γ09 00 •I 2ΖΓ61- Olf "6- 026 'OS 881 3 2HN 68 隱 VN 8Γ09 00I 2ΖΓ61- Olf "6- 026 'OS 881 3 2HN 68 Oki V
N 6ΖΌ9 00' 'I 8£f "6L- 9 ·6- 88L D OilV LHN 88Z9 H01VN 6ΖΌ9 00 '' I 8 £ f "6L- 9 6-88L D OilV LHN 88Z9 H01V
3 26*69 00 Ί 29 -ei- £9S"6- 992 '617 88L 0 DdV ZD 282S WO丄 V3 26 * 69 00 Ί 29 -ei- £ 9S "6- 992 '617 88L 0 DdV ZD 282S WO 丄 V
N 81 "89 00' Ί £9971- ZLl "01- lL9'6t7 881 3 DMV 3N 9829 W01VN 81 "89 00 'Ί £ 9971- ZLl" 01- lL9'6t7 881 3 DMV 3N 9829 W01V
3 8Z'6f 00' Ί S88"9l- z^roi- οεε'8 SSL 0 oav ao 9829 隱 V3 8Z'6f 00 'Ί S88 "9l- z ^ roi- οεε'8 SSL 0 oav ao 9829 Oki V
D 09'S 00' L t-90"6- 19"Ζ^ 881 3 03 WOiVD 09'S 00 'L t-90 "6- 19" Ζ ^ 881 3 03 WOiV
0 96'9£ 00' l 8£2'9l- SS£"8- 881 3 83 £82S 隱 V0 96'9 £ 00 'l 8 £ 2'9l- SS £ "8- 881 3 83 £ 82S Oki V
3 00' Ί £127- ιεε'^ 88L 3 vo W01V3 00 'Ί £ 127- ιεε' ^ 88L 3 vo W01V
N 6ΐ*ιε 00' L IL6'91- 6 ' 9 -
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881 3 N WOiVN 6ΐ * ιε 00 'L IL6'91- 6' 9-
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0 80 ε 00' I 298*91- 9Sに Z- Z8L D 0 0829 隨 V d 00· L 98E'9l- 89fr'9- 81 0 3 H01V0 80 ε 00 'I 298 * 91-9 to Z- Z8L D 0 0829 Exclusive V d 00L 98E'9l- 89fr'9- 81 0 3 H01V
N '89 00' L S99'f2- £80-9- 281 3 2HN WOIVN '89 00 'L S99'f2- £ 80-9- 281 3 2HN WOIV
N 00' I LZl^Z- 692'i- 890 'St^ 181 3 LHN H01VN 00 'I LZl ^ Z- 692'i- 890' St ^ 181 3 LHN H01V
3 10*89 00' L 669'£Z- 0L9'9- 890 Z81 D Z3 9229 WOiV3 10 * 89 00 'L 669' £ Z- 0L9'9- 890 Z81 D Z3 9229 WOiV
N 06 ^ 00· I 0 2 - 96L '9- 6 6'ε 281 3 3N WOIVN 06 ^ 00I 0 2-96L '9- 6 6'ε 281 3 3N WOIV
3 00· I W9- 288'^ Z81 D Q3 WOiV3 00I W9- 288 '^ Z81 D Q3 WOiV
D o 00' L £90*02- ZZ8'9- 9S9't^ Z8L 3 3iJV 3D WOIVD o 00 'L £ 90 * 02- ZZ8'9-9S9't ^ Z8L 3 3iJV 3D WOIV
3 00' I S88'8l - Zt7'9- Z81 3 93 H01V3 00 'I S88'8l-Zt7'9- Z81 3 93 H01V
3 00' I SL9 L- 9'S - UV^ Z81 3 V3 29 画3 00 'I SL9 L- 9'S-UV ^ Z81 3 V3 29 pictures
N f "L£ 00· L 909 'f- 6 ' 9 Z8L D 3HV N 0 29 H01V N f "L £ 00L 909 'f-6' 9 Z8L D 3HV N 0 29 H01V
9 Z I9 Z I
e.600/C00Zdf/X3d 0 02"6L 00 'I 999 "0 7- 969 ' t^ 56L 3 ao 9££9 WO丄 Ve.600 / C00Zdf / X3d 0 02 "6L 00 'I 999" 0 7- 969' t ^ 56L 3 ao 9 ££ 9 WO 丄 V
3 8871 00 ■I 990 Ό 988 •ε - εοο·6 961 0 yas vo 隠 V3 8871 00 ■ I 990 Ό 988 • ε-εοο6 961 0 yas vo hidden V
N 00*61 00 •I 199Ό- m 'ト 898 'if 961 D ϋョ s N εεε H01VN 00 * 61 00 • I 199Ό- m 'G 898' if 961 D D s N εεε H01V
0 00 Ί ZZZ'O- 10S •9- f29*8f Πί 3 dSV 0 NOiV0 00 Ί ZZZ'O-10S9- f29 * 8f Πί 3 dSV 0 NOiV
3 EE "0Z 00 •I 820Ί- 9Z9 •9- η 3 dSV 3 L££9 隱 V3 EE "0Z 00 • I 820Ί- 9Z9 • 9- η 3 dSV 3 L ££ 9 Hidden V
0 90 "02 00 •I Z91 "9- 6 •9- 28ε "St^ dSV ZQO OSES 隱 V0 90 "02 00 • I Z91" 9- 6 • 9- 28ε "St ^ dSV ZQO OSES Oki V
0 il'U 00 Ί 929"£- if6 •L- 86L '9f 3 dSV ιαο 62£9 隱 V0 il'U 00 Ί 929 "£-if6 • L-86L '9f 3 dSV ιαο 62 £ 9 Oki V
0 ί'ΖΖ 00 'I 690't^- Z06 •9 - πι 3 dSV DO 82£9 W01V0 ί'ΖΖ 00 'I 690't ^-Z06 • 9-πι 3 dSV DO 82 £ 9 W01V
0 69 ΌΖ 00 ■I PLZ'i- £02 •9- S08"9t^ 61 3 dSV IZiS 隠 V0 69 ΌΖ 00 ■ I PLZ'i- £ 02 • 9- S08 "9t ^ 61 3 dSV IZiS Hidden V
3 0 ·02 00 Ί 98 Ί- f60 ■9- ^61 3 dSV o 92E9 隱 V3 0 · 02 00 Ί 98 Ί- f60 ■ 9- ^ 61 3 dSV o 92E9 Oki V
N 26 "02 00 'I L99"l- 091 '9- 88E ' f f6l 3 dSV N 92£9 H01VN 26 "02 00 'I L99" l-091' 9-88E 'f f6l 3 dSV N 92 £ 9 H01V
0 60"12 00' Ί ^WQ 6^2 '9- Z69 E6L 0 AID 0 S INOiV0 60 "12 00 'Ί ^ WQ 6 ^ 2' 9- Z69 E6L 0 AID 0 S INOiV
0 80·0Ζ 00' Ί WO- LOi '9- Ot-9 'n £61 D AID 3 隱 V0 8000 Ζ 00 'Ί WO- LOi' 9- Ot-9 'n £ 61 D AID 3 Oki V
3 00' Ί 60 ·0- Z Z'P- £61 0 人 13 vo WOiV3 00 'Ί 60 · 0- Z Z'P- £ 61 0 13 vo WOiV
N Zi'8l 00' Ί 680 Ί- 810 'ε- 098 "Sfr £61 3 人 13 N £9 W01VN Zi'8l 00 'Ί 680 Ί- 810' ε- 098 "Sfr £ 61 3 13 N £ 9 W01V
0 0 02 00' Ί L\ri- 6L£ •ε- ' Z6L 3 N13 0 0Z£9 WO丄 V d '6l 00' Ί Z'Z- ZS9 ■2 - 9εζ'ε 261 0 N，3 3 6l£9 W01V0 0 02 00 'Ί L \ ri- 6L £ • ε-' Z6L 3 N13 0 0Z £ 9 WO 丄 V d '6l 00' Ί Z'Z- ZS9 ■ 2-9εζ'ε 261 0 N, 3 3 6l £ 9 W01V
N i£"6l 00' ■I £82*9- 926*0 261 3 N10 23N 8l£9 INOIVN i £ "6l 00 '■ I £ 82 * 9- 926 * 0 261 3 N10 23N 8l £ 9 INOIV
0 00' Ί 0£9 •ζ 891 261 0 ΝΊ3 L30 il£ 隠 V0 00 'Ί 0 £ 9 • ζ 891 261 0 ΝΊ3 L30 il £ hidden V
3 f8'02 00' Ί m' - 929 •I 丄 9 ' Ζ61 3 ΝΊΟ ao 9l£9 WO丄 V3 f8'02 00 'Ί m'-929I 丄 9 'Ζ61 3 ΝΊΟ ao 9l £ 9 WO 丄 V
0 ^fZZ 00' Ί L98 - £f L •L 3 ΝΊ3 93 9l£9 隠 V0 ^ fZZ 00 'Ί L98-£ f LL3 ΝΊ3 93 9l £ 9 hidden V
0 £9 1 00' Ί 66 2- 92£ ■0 - 189 ' Z6L 3 N，3 93 匿 V0 £ 9 1 00 'Ί 66 2-92 £ ■ 0-189' Z6L 3 N, 3 93 Secret V
0 6£7l 00' ■I 698"Z- 09S •l- 2 'ε 36 L 0 N19 V3 WO丄 V0 6 £ 7l 00 '■ I 698 "Z- 09S • l-2' ε 36 L 0 N19 V3 WO 丄 V
N 99'ZL 00' Ί 619 'l- 801 ' 261 3 ΝΊ3 N WO丄 VN 99'ZL 00 'Ί 619' l- 801 '261 3 ΝΊ3 N WO 丄 V
0 06 -OZ 00' Ί •ε - 161 0 SAO 0 IL89 W01V0 06 -OZ 00 'Ί • ε-161 0 SAO 0 IL89 W01V
3 S8'8L 00' Ί 'Ρ- 1997- 988 ' L6L 0 SAO 3 0l£S NOIV3 S8'8L 00 'Ί' Ρ- 1997- 988 'L6L 0 SAO 3 0l £ S NOIV
S Ζΐ'ΖΖ 00' Ί 012 - 689 •l - 988 ' L6L 0 SAO DS 60£9 INOIVS Ζΐ'ΖΖ 00 'Ί 012-689 l-988' L6L 0 SAO DS 60 £ 9 INOIV
3 2に 61 00' Ί ε 9- 9S0'£- 206 ·ε 161 3 SAO 90 80SS W01V3 2 to 61 00 'ε ε 9-9S0' £-206 ・ ε 161 3 SAO 90 80SS W01V
0 91·81 00' Ί 890 '9- ~z- 丄 61 'S 161 3 SAO VO Z0£9 隱 V0 9181 00 'Ί 890' 9- ~ z- 丄 61 'S 161 3 SAO VO Z0 £ 9 Oki V
N £Z'9L 00' Ί 60£'9- 260 "9^ 161 0 SAO N 9089 隠 VN £ Z'9L 00 'Ί 60 £' 9- 260 "9 ^ 161 0 SAO N 9089 hidden V
0 89"6l 00' Ί 282 "8- 280 1 '^ 06 L 0 d3S 0 S0E9 隱 V0 89 "6l 00 'Ί 282" 8-280 1' ^ 06 L 0 d3S 0 S0E9 Oki V
0 00' Ί 'L- 686 'ε - 98Z"9fr 061 D M3S 0 S 隱 V0 00 'Ί' L-686 'ε-98Z "9fr 061 D M3S 0 S Oki V
0 00' Ί ·9— L98'£- 061 0 90 S0S9 隠 V 0 00 'Ί · 9— L98' £-061 0 90 S0S9 Hidden V
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00/£00ZdT/lDd 0 90 2 00· I ειε·2 - Ζ96Ί 08ε ·ε 96 α ϋΗ丄 LDO WOiV 0 98*12 OO'l ΖΖΟΊ 009 "Ζ 96 α ΗΗ丄 eo z 鼠 V 3 εε·8ΐ oo'L 818Ί- Ζ8£Ό- 2967 96 α m丄 o WOiV N i a oo'i 606 - 198Ό- 96 α mi N 0^9 WOIV 0 Lに 61 OO'l £99 'f- m'Q- Μ9·ε S6 α a人丄 0 6ε 9 WOIV 0 Z9*8l OO'l 081 ' ー l£8'0- 8097 S6 α a人丄 3 H01V 0 60· OO'l S '8- Z£S.£ Μ6'ε 6 α iU丄 HO WOIV 3 6Z" L OO'L 8297- 999*2 060 "£ 6 α ¾1人丄 Z3 H01V 3 OO'l 982 '9- Ζ86 Ί 999 '2 6 α a人丄 233 WOIV 0 20, SI OO'l £99*9- 180 S89'l 6 α a人丄 203 9 WOIV 0 £9"9L OO'l W8- ' ·Ζ 96 α a人丄 133 WOIV 3 90' OO'l 6297- WO 868"L 96 α ιαο H01V 3 99'9L OO'L ZLZ^- 98·0 19ΓΙ 6 α y人丄 33 WOiV 3 £2'EL OO'L 0t?9 "9- 18L ·0- Ζ99"0 .96. α a人丄 93 οε 9 WOIV 0 98"8l OO'l fril '9- O 'L- I 96 α il人丄 VO 6 9 WOiV N 66'il 00" I 9i9-f- 89 - 18 0 96 α a人丄 N 8 9 WOIV 0 t'S 'ζΖ 00 "L 92S'9- 9ZS ·£- 89S"0 6 αョ Hd 0 9 WOIV 0 99 2 OO'l 10£'9- 9L9 'ε- 80 ' 0 6 αョ Hd 3 9Zfr9 H01¥ 3 il'ZZ OO'l 6ΐ *ε- 6 αョ Hd 1 S 9 H01V 3 8£'8l OO'l 6 αョ Hd 23D 9 WOIV 3 £8 1 OO'l ZiE'Z- £6·ε- 9 9·ε t^6 αョ Hd 130 WOIV 3 60*12 OO'l l£6-f- 0£6^- 88に ε f6 α 3Hd ZQ zm WOIV 0 00'6l OO'L 6997- 689't^- ^2 6 αョ Hd IQO I 9 WOIV 3 I ΊΙ OO'l 8 6·ε- 680*9- 60Γ2 6 αョ Hd DO 02 WOIV D LVOZ OO'L 882-f- Z02"9- 8i8"0 6 αョ Hd 90 61^9 WOIV 3 09'£2 OO'l l9"fr- 2'0- 6 α 3Hd V3 8 9 H01V N P'5Z OO'l SZO'S- Z82"9- ' I - π αョ Hd N WOIV 0 60'62 OO'l L99"0L- 199Έ- 816' νο9 α Odd 0 οεΐ9 HO丄 V D ·92 OO'l £89 "6- 'ε- 8^9 '9 νο9 α 0 6219 WOIV 0 L^' OO'L LZP'L- εο6"ο- 9St "S νο9 α oad 03 8219 WOIV D 86·ε2 OO'l 3867- 6 6·1- LiZ^ νο9 α ao 9 WOIV 0 ΖΙ'Π OO'L 2£ 8- ΖΖΙ'ΐ- V09 α VD 9Z19 HOiV D 9· OO'l 69 ' 9— £00"9 V09 α Q3 9219 WOIV
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C,600/COOZdf/X3d 表 7 (その 29) C, 600 / COOZdf / X3d Table 7 (Part 29)
ATOM 6444 CG2 THR D 96 2. 796 1.363 -0.036 1. .00 CATOM 6444 CG2 THR D 96 2.796 1.363 -0.036 1. .00 C
ATOM 6445 C THR D 96 2. 726 -1.272 - 0.585 1. .00 19.01 CATOM 6445 C THR D 96 2.726 -1.272-0.585 1. .00 19.01 C
ATOM 6446 0 THR D 96 1. 603 -1.713 -0.344 1. .00 18.18 0ATOM 6446 0 THR D 96 1.603 -1.713 -0.344 1. .00 18.18 0
ATOM 6447 N ALA D 97 3. 770 -1.524 0.202 1. .00 17.21 NATOM 6447 N ALA D 97 3.770 -1.524 0.202 1. .00 17.21 N
ATOM 6448 CA ALA D 97 3. 620 -2.363 1.395 1, .00 17.28 CATOM 6448 CA ALA D 97 3.620 -2.363 1.395 1, .00 17.28 C
ATOM 6449 CB ALA D 97 4. 988 -2.664 2.020 1. ,00 15.98 CATOM 6449 CB ALA D 97 4.988 -2.664 2.020 1., 00 15.98 C
ATOM 6450 C ALA D 97 2. 699 -1.752 2.452 1. .00 18.99 cATOM 6450 C ALA D 97 2.699 -1.752 2.452 1. .00 18.99 c
ATOM 6451 0 ALA D 97 2. 055 -2.484 3.207 1. ,00 14.38 0ATOM 6451 0 ALA D 97 2.055 -2.484 3.207 1., 00 14.38 0
ATOM 6452 N GLN D 98 2. 648 -0.418 2.517 1. ,00 18.42 NATOM 6452 N GLN D 98 2.648 -0.418 2.517 1., 00 18.42 N
ATOM 6453 CA GLN D 98 1. 798 0.252 3.496 1. .00 19.96. CATOM 6453 CA GLN D 98 1.798 0.252 3.496 1. .00 19.96.C
ATOM 6454 CB GLN D 98 2. 186 1.726 3.635 1. ,00 22.06 CATOM 6454 CB GLN D 98 2.186 1.726 3.635 1., 00 22.06 C
ATOM 6455 CG GLN D 98 3. 596 1.952 4.167 1. .00 23.15 CATOM 6455 CG GLN D 98 3.596 1.952 4.167 1. .00 23.15 C
ATOM 6456 CD GLN D 98 4.661 1.589 3.146 1. ,00 23.11 CATOM 6456 CD GLN D 98 4.661 1.589 3.146 1., 00 23.11 C
ATOM 6457 0E1 GLN D 98 4. 549 1.939 1.972 1. .00 16.41 0ATOM 6457 0E1 GLN D 98 4.549 1.939 1.972 1. .00 16.41 0
ATOM 6458 NE2 GLN D 98 5. 706 0.899 3.594 1. ,00 18.13 NATOM 6458 NE2 GLN D 98 5.706 0.899 3.594 1., 00 18.13 N
ATOM 6459 C GLN D 98 0. 322 0.127 3.120 1. .00 ro 20.08 CATOM 6459 C GLN D 98 0.322 0.127 3.120 1. .00 ro 20.08 C
ATOM 6460 0 GLN D 98 -0. 551 0.164 3.985 1. ,00 19.09 0ATOM 6460 0 GLN D 98 -0.551 0.164 3.985 1., 00 19.09 0
ATOM 6461 N ILE D 99 0. 053 一 0.018 1.825 1. ,00 19.66 NATOM 6461 N ILE D 99 0.053 1 0.018 1.825 1., 00 19.66 N
ATOM 6462 CA ILE D 99 - 1. 311 -0.187 1.351 1. ,00 19.71 cATOM 6462 CA ILE D 99-1. 311 -0.187 1.351 1., 00 19.71 c
ATOM 6463 CB ILE D 99 - 1. 434 0.142 - 0.155 1. ,00 18.36 cATOM 6463 CB ILE D 99-1.434 0.142-0.155 1., 00 18.36 c
ATOM 6464 CG2 ILE D 99 -2. 829 -0.212 -0.654 1. .00 17.96 cATOM 6464 CG2 ILE D 99 -2.829 -0.212 -0.654 1. .00 17.96 c
ATOM 6465 CG1 ILE D 99 - 1. 146 1.632 -0.374 1. ,00 19.75 cATOM 6465 CG1 ILE D 99-1.146 1.632 -0.374 1., 00 19.75 c
ATOM 6466 cm ILE D 99 - 1. 040 2.055 -1.826 1. ,00 14.82 cATOM 6466 cm ILE D 99-1. 040 2.055 -1.826 1., 00 14.82 c
ATOM 6467 C ILE D 99 - 1. 711 -1.641 1.593 1. 00 20.70 cATOM 6467 C ILE D 99-1.711 -1.641 1.593 1.00 20.70 c
ATOM 6468 0 ILE D 99 -2.869 -1.931 1.889 1. ,00 21.63 0ATOM 6468 0 ILE D 99 -2.869 -1.931 1.889 1., 00 21.63 0
ATOM 6469 N GLY D 100 -0.747 -2.553 1.472 1. 00 18.64 HATOM 6469 N GLY D 100 -0.747 -2.553 1.472 1.00 18.64 H
ATOM 6470 CA GLY D 100 - 1· 038 - 3.956 1.711 1. 00 16.87 cATOM 6470 CA GLY D 100-1.038-3.956 1.711 1.00 16.87 c
ATOM 6471 C GLY D 100 -0.846 -4.892 0.535 1. 00 17.20 cATOM 6471 C GLY D 100 -0.846 -4.892 0.535 1.00 17.20 c
ATOM 6472 0 GLY D 100 -0. 332 -4.495 -0.520 1. 00 13.11 0ATOM 6472 0 GLY D 100 -0.33 -4.495 -0.520 1.00 13.11 0
ATOM 6473 N ALA D 101 -1. 270 -6.143 0.730 1. 00 16.50 NATOM 6473 N ALA D 101 -1. 270 -6.143 0.730 1.00 16.50 N
ATOM 6474 CA ALA D 101 -1. 146 -7.198 -0.279 1. 00 15.86 CATOM 6474 CA ALA D 101 -1. 146 -7.198 -0.279 1.00 15.86 C
ATOM 6475 CB ALA D 101 -2. 013 -6.875 -1.502 1. 00 12.19 CATOM 6475 CB ALA D 101 -2.0.13 -6.875 -1.502 1.00 12.19 C
ATOM 6476 C ALA D 101 0. 311 -7.385 -0.700 1. 00 15.45 c 0 OS'92 OO'l Z8S'6l 8S27- OSS "91 281 α 0 ZUL W01V 3 Ll'LZ OO'l Z98"6l S£9-9- 6L9 "SI Z8L G DilV 0 102Z WOiV N 99 " S OO'L εε 92 εζ6·ε- 8· m α oav HN 0021 隱 V N 8S OO'l rn'iz 89に 9 - 22に SI Z81 α oav LHN 66 WOIV 3 6t^ S 00 Ί 962 "92 Pll 'S - 026 l 281 α雷 Z3 86U WOIV N 29^9 OO'l 266 Z ιε - £16 · α 3N Z6li WOiV 3 20*09 OO'l n 89 9 - i00'9l α QO 9611 INOIV 3 8 'ε OO'L L06 2 ζε 9- 608· L α oa DO 96U WOIV 3 sに ιε οο'ι IWZZ £68 "91 281 G資 80 n WOIV 3 9672 OO'L SSf9- 899 "91 181 α V 96L1 WOIV N 9ε· oo'i 9 a oav N WOIV 0 06-8l OO'l 91 Ε- 618Ή- 102'9 a viv 0 86^9 WOIV 3 9671 OO'l 96271- 622 G viv 0 i WOIV 3 9fil OO'l m'v- ~ii- ζ'^ a viv 83 96179 WOIV 0 ■91 OO'l izz^- 898'2L- a v，v V3 96^9 WOiV N 89*91 OO'L 丄 98'2- 0 ·21- 0^6 '£ t^OL a viv N WOiV 0 99"Sl OO'l 6·01 - εοι a 3i 1 0 WOIV 3 1671 OO'l 21^-11- 8 ο'ε εοι a 311 3 z WOIV 3 ο'ει οο'ι 96 ■() 6εο·Μ- 120*1 εοι a an mo 16179 H01V 0 2£"9L OO'L 9lf "0- 666 *1 εοι a 311 LCD 06 9 WOIV 3 Zi "91 OO'l Wl- 169Ί1- εοι a 311 333 68^9 WOIV 3 6ΓΕΙ OO'l 989*0- 9£8"Ll- iS9'l εοι a 311 83 88^9 H01V 0 8に ει oo'i 261 "l- 690"Ll- £S8'2 901 a 3i 1 VO 8f9 WOIV N 92 "frl OO'L 60·1 - 9£9'6- 629 εοι Q ΞΊΙ N 98^9 WOIV 0 0971 OO'l WO 68 ·6 - ·ε 201 a dsv 0 981^9 WOIV 3 09*91 OO'l UO'O- Ζ96"8- 丄 86 201 a dsv 0 9 WOIV 0 EL 'LI OO'l ^ *1 666 "9- 999 *9 201 a dsv 200 £81?9 WOiV 0 EO'lL OO'L WO- 906 '9- 201 a dsv ιαο 28^9 WOiV 0 £Z'9l 00 Ί 989 "0 8£S'9- ζοι a dsv 33 18 9 WOiV d I OO'l 890'1 9£Z"9- 201 a dsv 93 08f9 WOIV 3 OO'l ειο'ο - £997 201 a dsv VO 6 9 WOiV N Z9'9L OO'l 192Ό -L- 201 a dsv H 9 隱 V 0 ε ·8ΐ oo'i 898 Ί- 2197- 09,0 10L a viv 0 Lm HOiV ATOM 6476 C ALA D 101 0.31 -7.385 -0.700 1.00 15.45 c 0 OS'92 OO'l Z8S'6l 8S27- OSS "91 281 α 0 ZUL W01V 3 Ll'LZ OO'l Z98" 6l S £ 9-9-6L9 "SI Z8L G DilV 0 102Z WOiV N 99" S OO 'L εε 92 εζ6 ・ ε- 8 ・ m α oav HN 0021 Hidden VN 8S OO'l rn'iz 89 to 9-22 SI Z81 α oav LHN 66 WOIV 3 6t ^ S 00 962 962 "92 Pll' S- 026 l 281 α thunder Z3 86U WOIV N 29 ^ 9 OO'l 266 Z ιε-£ 16α 3N Z6li WOiV 3 20 * 09 OO'l n 89 9-i00'9l α QO 9611 INOIV 3 8 'ε OO' L L06 2 ζε 9- 608 L α oa DO 96U WOIV 3 s ιε οο'ι IWZZ £ 68 "91 281 G capital 80 n WOIV 3 9672 OO'L SSf9- 899" 91 181 α V 96L1 WOIV N 9ε oo'i 9 a oav N WOIV 0 06-8l OO'l 91 Ε- 618Ή- 102'9 a viv 0 86 ^ 9 WOIV 3 9671 OO'l 96271- 622 G viv 0 i WOIV 3 9fil OO'l m ' v- ~ ii- ζ '^ a viv 83 96179 WOIV 0 ■ 91 OO'l izz ^-898'2L- av, v V3 96 ^ 9 WOiV N 89 * 91 OO'L 丄 98'2- 0 0 ^ 6 '£ t ^ OL a viv N WOiV 0 99 "Sl OO'l 601-εοι a 3i 1 0 WOIV 3 1671 OO'l 21 ^ -11- 8 ο'ε εοι a 311 3 z WOIV 3 ο'ει οο'ι 96 ■ () 6εο · Μ- 120 * 1 εοι a an mo 16179 H01V 0 2 £ "9L OO'L 9lf" 0- 666 * 1 εοι a 311 LCD 06 9 WOIV 3 Zi "91 OO'l Wl- 169Ί1- εοι a 311 333 68 ^ 9 WOIV 3 6ΓΕΙ OO'l 989 * 0- 9 £ 8" Ll- iS9'l εοι a 311 83 88 ^ 9 H01V 0 8 to ει oo'i 261 "l-690" Ll- £ S8'2 901 a 3i 1 VO 8f9 WOIV N 92 "frl OO'L 60 · 1-9 £ 9'6- 629 εοι Q ΞΊΙ N 98 ^ 9 WOIV 0 0971 OO'l WO 686-6-e 201 a dsv 0 981 ^ 9 WOIV 3 09 * 91 OO'l UO'O- Ζ96 "8- 丄 86 201 a dsv 0 9 WOIV 0 EL 'LI OO 'l ^ * 1 666 "9-999 * 9 201 a dsv 200 £ 81? 9 WOiV 0 EO'lL OO'L WO- 906' 9- 201 a dsv ιαο 28 ^ 9 WOiV 0 £ Z'9l 00 Ί 989 "0 8 £ S'9- ζοι a dsv 33 18 9 WOiV d I OO'l 890'1 9 £ Z" 9- 201 a dsv 93 08f9 WOIV 3 OO'l ειο'ο-£ 997 201 a dsv VO 6 9 WOiV N Z9'9L OO'l 192Ό -L- 201 a dsv H 9 Oki V 0 ε8ΐ oo'i 898 Ί- 2197- 09,0 10L a viv 0 Lm HOiV
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38 表 7 (その 34)  38 Table 7 (Part 34)
ATOM 7420 CA GLY D 219 13.014 10.819 1. .00 15.72 CATOM 7420 CA GLY D 219 13.014 10.819 1. .00 15.72 C
ATOM 7421 C GLY D 219 13.025 -0.104 11.433 1. .00 20.38 CATOM 7421 C GLY D 219 13.025 -0.104 11.433 1. .00 20.38 C
ATOM 7422 0 GLY D 219 12.152 -0.947 11.169 1. ,00 17.71 0ATOM 7422 0 GLY D 219 12.152 -0.947 11.169 1., 00 17.71 0
ATOM 7423 N CYS D 220 14.016 - 0.339 12.283 1. ,00 20.68 NATOM 7423 N CYS D 220 14.016-0.339 12.283 1., 00 20.68 N
ATOM 7424 CA CYS D 220 14.174 12.913 1, .00 20.70 CATOM 7424 CA CYS D 220 14.174 12.913 1, .00 20.70 C
ATOM 7425 CB CYS D 220 15.368 -2.345 12.275 1. ,00 20.86 CATOM 7425 CB CYS D 220 15.368 -2.345 12.275 1., 00 20.86 C
ATOM 7426 SG CYS D 220 15.325 -2.283 10.453 1. ,00 19.33 SATOM 7426 SG CYS D 220 15.325 -2.283 10.453 1., 00 19.33 S
ATOM 7427 C CYS D 220 14.388 -1.472 14.410 1, ,00 22.02 CATOM 7427 C CYS D 220 14.388 -1.472 14.410 1,, 00 22.02 C
ATOM 7428 0 CYS D 220 15.206 -0.664 14.839 1. ,00 22.71 0ATOM 7428 0 CYS D 220 15.206 -0.664 14.839 1., 00 22.71 0
ATOM 7429 N ALA D 221 13.632 -2.239 15.192 1. .00 24.24 NATOM 7429 N ALA D 221 13.632 -2.239 15.192 1. .00 24.24 N
ATOM 7430 CA ALA D 221 13.723 -2.22 f3— 16.651 1, .00 25.75 CATOM 7430 CA ALA D 221 13.723 -2.22 f3— 16.651 1, .00 25.75 C
ATOM 7431 CB ALA D 221 15.057 -2.837 17.104 1. .00 21.96 CATOM 7431 CB ALA D 221 15.057 -2.837 17.104 1. .00 21.96 C
ATOM 7432 C ALA D 221 13.559 -0.830 17.249 1. .00 24.98 cATOM 7432 C ALA D 221 13.559 -0.830 17.249 1. .00 24.98 c
ATOM 7433 0 ALA D 221 14.193 - 0.489 18.245 1. .00 26.03 0ATOM 7433 0 ALA D 221 14.193-0.489 18.245 1. .00 26.03 0
ATOM 7434 N GLN D 221A 12.711 -0.023 16.631 1. ,00 27.16 NATOM 7434 N GLN D 221A 12.711 -0.023 16.631 1., 00 27.16 N
ATOM 7435 CA GLN D 221A 12.456 1.322 17.122 1. .00 27.75 cATOM 7435 CA GLN D 221A 12.456 1.322 17.122 1. .00 27.75 c
ATOM 7436 CB GLN D 221A 12.319 2.286 15.942 1. .00 31.95 cATOM 7436 CB GLN D 221A 12.319 2.286 15.942 1. .00 31.95 c
ATOM 7437 CG GLN D 221A 13.644 2.608 15.250 1, ,00 38.67 cATOM 7437 CG GLN D 221A 13.644 2.608 15.250 1,, 00 38.67 c
ATOM 7438 CD GLN D 221A 13.484 3.658 14.163 1. .00 42.81 cATOM 7438 CD GLN D 221A 13.484 3.658 14.163 1. .00 42.81 c
ATOM 7439 0E1 GLN D 221A 12.821 4.676 14.360 1. ,00 47.47 0ATOM 7439 0E1 GLN D 221A 12.821 4.676 14.360 1., 00 47.47 0
ATOM 7440 NE2 GLN D 221A 14.100 3.421 13.013 1. .00 48.12 NATOM 7440 NE2 GLN D 221A 14.100 3.421 13.013 1. .00 48.12 N
ATOM 7441 C GLN D 221A 11.196 1.341 18.003 1. ,00 27.12 cATOM 7441 C GLN D 221A 11.196 1.341 18.003 1., 00 27.12 c
ATOM 7442 0 GLN D 221A 10.227 0.601 17.761 1. ,00 23.83 0ATOM 7442 0 GLN D 221A 10.227 0.601 17.761 1., 00 23.83 0
HETATM 7641 N1 NAN D 301 9.120 -1.094 - 0.669 1. .00 24.48 NHETATM 7641 N1 NAN D 301 9.120 -1.094-0.669 1. .00 24.48 N
HETATM 7642 CI 麵 D 301 10.231 -0.213 -0.328 1. ,00 19.68 cHETATM 7642 CI 麵 D 301 10.231 -0.213 -0.328 1., 00 19.68 c
HETATM 7643 C2 麵 D 301 Π.278 -0.860 0.592 1. , 00 22.33 cHETATM 7643 C2 麵 D 301 Π.278 -0.860 0.592 1., 00 22.33 c
HETATM 7644 SI 麵 D 301 7.553 -0.481 -0.326 1. ,00 22.14 sHETATM 7644 SI 麵 D 301 7.553 -0.481 -0.326 1., 00 22.14 s
HETATM 7645 01 NAN D 301 6.477 -1.498 -0.716 1. ,00 26.83 0HETATM 7645 01 NAN D 301 6.477 -1.498 -0.716 1., 00 26.83 0
HETATM 7646 02 NAN D 301 7.381 -0.212 1.179 1. ,00 23.82 0HETATM 7646 02 NAN D 301 7.381 -0.212 1.179 1., 00 23.82 0
HETATM 7647 C3 NAN D 301 6.089 1.991 -4.660 1. 00 18.13 cHETATM 7647 C3 NAN D 301 6.089 1.991 -4.660 1.00 18.13 c
HETATM 7648 C4 麵 D 301 5.841 3.159 -5.379 1. 00 18.54 cHETATM 7648 C4 麵 D 301 5.841 3.159 -5.379 1.00 18.54 c
HETATM 7649 C5 NAN D 301 6.032 4.431 -4.776 1. 00 18.65 cHETATM 7649 C5 NAN D 301 6.032 4.431 -4.776 1.00 18.65 c
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29 '92 00' L 118 ,11 L8E"£l- 612"9£ H0H 0 S9ZZ H1V13H29 '92 00 'L 118, 11 L8E "£ l-612" 9 £ H0H 0 S9ZZ H1V13H
88 l 00' Ί 60 I W 28 H0H 0 PSIL W丄 V丄ョ H88 l 00 'Ί 60 I W 28 H0H 0 PSIL W 丄 V 丄 H
6^ 2 00' Ί 8iS*6 89 l- L8 H0H 0 E9ZZ H1V13H6 ^ 200 'Ί 8iS * 6 89 l- L8 H0H 0 E9ZZ H1V13H
^'Π 00' L Z9t? '£L- 999'L- 8S0*09 08 ■ 0 ZSU 隱ョ H^ 'Π 00' L Z9t? '£ L- 999'L-8S0 * 09 08 ■ 0 ZSU Oki H
0L"02 00' Ί Z21 ,8- 6 H0H 0 L9ZZ0L "02 00 'Ί Z21, 8-6 H0H 0 L9ZZ
£672 00' 'L ε 8 •ει lOS'Sl- nvu L H0H 0 09ZZ W1V13H £ 672 00 '' L ε 8 • ει lOS'Sl- nvu L H0H 0 09ZZ W1V13H
(8ε O) ）乙拏 (8ε O)) Halla
z 0 00'8£ 00 'ι 89Z"l 01^*9- ε^9 HOH 0 918Z 匪ョ Hz 0 00'8 £ 00 'ι 89Z "l 01 ^ * 9- ε ^ 9 HOH 0 918Z
0 ' Z 00 •ι Zll Ό Z69'99 S ■ 0 隱ョ H0 'Z 00 • ι Zll Ό Z69'99 S ■ 0 Oki H
0 t79'9S 00 •ι 9·9- 98.91- 6£8·92 lt^9 HOH 0 W1V13H0 t79'9S 00 • ι 9.9- 98.91- 6 £ 892 lt ^ 9 HOH 0 W1V13H
0 8 ιε 00 Ί ζεπι- L89"l 986 'S 0t^9 HOH 0 Z121 隱丄ョ H0 8 ιε 00 Ί ζεπι- L89 "l 986 'S 0t ^ 9 HOH 0 Z121 Oki H
0 00 •ι 9G1"SI- '6 6E9 HOH 0 H2L 丄ョ H0 00 • ι 9G1 "SI- '6 6E9 HOH 0 H2L
0 28 "ZZ 00 •ι ιεε"6ΐ £6£·8 8£9 HOH 0 0182 H1V13H0 28 "ZZ 00 • ι ιεε" 6ΐ £ 6 £ · 8 8 £ 9 HOH 0 0182 H1V13H
0 9Z'92 00 ■ι 28 ·ε 062"l Z£9 HOH 0 6082 隱丄ョ H0 9Z'92 00 ■ ι 28 · ε 062 "l Z £ 9 HOH 0 6082 Okiyo H
0 H'^Z 00 •ι οε ' 9ΐ m'Qz- 1 6fr 9£9 HOH 0 8081 丄ョ H0 H '^ Z 00 • ι οε' 9ΐ m'Qz- 1 6fr 9 £ 9 HOH 0 8081
0 ΖΓ9Ε 00 •ι u n- 280 ·0 - 9£S HOH 0 Z082 匪ョ H0 ΖΓ9Ε 00 • ι u n- 280 · 0-9 £ S HOH 0 Z082 Marauder H
0 10·82 00 ■ι 6εε·2- 9L6 1 Hi HOH 0 9081 丄ョ H0 1082 00 ■ ι 6εε2-9L6 1 Hi HOH 0 9081
0 WU 00 'ι 699-2L- εοΓ - 10に 0 ££9 HOH 0 9081 H1V13H0 WU 00 'ι 699-2L- εοΓ-10 to 0 ££ 9 HOH 0 9081 H1V13H
0 88· ε 00' Ί si ·ει - £2£'Sl HOH 0 P02L W1V13H0 88ε 00 'Ί siεε-£ 2 £' Sl HOH 0 P02L W1V13H
0 89·02 00 L 960"6L 929Έ- 919 -f 9 L£9 HOH 0 £082 H1V13H0 8902 00 L 960 "6L 929Έ- 919 -f 9 L £ 9 HOH 0 £ 082 H1V13H
0 'Ll 00' Ί 10Γ9- 0S9 HOH 0 2081 W1V13H0 'Ll 00' Ί 10Γ9- 0S9 HOH 0 2081 W1V13H
0 66'0£ 00 ' Ί 98'ει 6£8'92- m ·ο- 62S HOH 0 1082 W1V13H0 66'0 £ 00 'Ί 98'ει 6 £ 8'92- mo-62S HOH 0 1082 W1V13H
0 69'9Z 00' Ί IIV%1 829 HOH 0 008 隱丄ョ H0 69'9Z 00 'Ί IIV% 1 829 HOH 0 008 Oki H
0 18·12 00' Ί 8££'0L- 9 '9- 6L9"19 12 HOH 0 66Z1 匪ョ H0 18 · 12 00 'Ί 8 ££' 0L- 9 '9- 6L9 "19 12 HOH 0 66Z1 Marauder H
0 00' L 61 962 9Z9 HOH 0 86ΖΖ WiViHH0 00 'L 61 962 9Z9 HOH 0 86ΖΖ WiViHH
0 99*IE 00' 'ι 099 L ' 81 '丄 929 HOH 0 隱ョ H0 99 * IE 00 '' ι 099 L '81' 丄 929 HOH 0 Oki H
0 εε'ιε 00' L Z9i'6 092 "9£ 986 '9 HOH 0 9621 W1V13H0 εε'ιε 00 'L Z9i'6 092 "9 £ 986' 9 HOH 0 9621 W1V13H
0 ε8·εε 00' 1 £92'9L- 91ΖΌ HOH 0 S6" IN1V13H0 ε8 · εε 00 '1 £ 92'9L- 91ΖΌ HOH 0 S6 "IN1V13H
0 00 ' Ί ££6'6- W6- 06に 91 229 HOH 0 a隨丄ョ H0 00 'Ί ££ 6'6- W6- 06 to 91 229 HOH 0 a
0 06 "92 00' 1 068·1 - 69に L29 HOH 0 £6 i H1V13H0 06 "92 00 '1 0681-69 to L29 HOH 0 £ 6 i H1V13H
0 90*εζ 00" L i£8'E2 081 'L εοε'ε 029 HOH 0 26 W1V13H0 90 * εζ 00 "L i £ 8'E2 081 'L εοε'ε 029 HOH 0 26 W1V13H
0 81 ·82 00' 1 8 171 099*01- 61S HOH 0 16 匪ョ H0 81 82 0 '1 8 171 099 * 01- 61S HOH 0 16 Marauder H
0 ζο'οε 00' L 80971 l^'ll 69£ 7- 8L9 HOH 0 06/ 隱ョ H0 ζο'οε 00 'L 80971 l ^' ll 69 £ 7-8 L9 HOH 0 06 / Oki H
0 6ε·εζ 00 ' 1 88ε ·9 IIS HOH 0 68" 隱丄ョ hi0 6ε · εζ 00 '1 88ε · 9 IIS HOH 0 68 "Oki hi
0 00" 1 £9S'6- 'l 060 "OS 91S HOH 0 88" WIV13H0 00 "1 £ 9S'6- 'l 060" OS 91S HOH 0 88 "WIV13H
0 ^'Π 00" L 600 '9 296"8L Ε96· 9 9L9 HOH 0 mi隱ョ H0 ^ 'Π 00 "L 600' 9 296" 8L Ε96 · 9 9L9 HOH 0 mi Oki H
0 ΙΙΊΙ 00' 1 S 6·9 ΐ8ε·ε - 'L- H HOH 0 98" H1V13H0 ΙΙΊΙ 00 '1 S 6.9 ΐ8ε ·-' L- H HOH 0 98 "H1V13H
0 16'61 00' L 998 "0- 696 "81 £19 HOH 0 9811 隱ョ H0 16'61 00 'L 998 "0- 696" 81 £ 19 HOH 0 9811 Oki H
0 81 00" L εθΓΟΙ 9S9"S2 090 ' 2LS HOH 0 隱ョ H0 81 00 "L εθΓΟΙ 9S9" S2 090 '2LS HOH 0 Oki H
0 00' 1 192 L- 2 8 '6 99£ '6 119 HOH 0 隱ョ H 0 00 '1 192 L- 2 8' 6 99 £ '6 119 HOH 0 Oki H
e/,600/f00 dT/X3d t" Π0 00£ OAV 0 £2'6l 00 Ί ·0 - ε8ε· - 900, Si 929 HOH 0 8 H1V13He /, 600 / f00 dT / X3d t "Π0 00 £ OAV 0 £ 2'6l 00 Ί 0-ε8ε-900, Si 929 HOH 0 8 H1V13H
0 28 2 00 •ι 66ε· ι 980.85 S 9 HOH 0 mi W1V13H0 28 2 00 • ι 66ει 980.85 S 9 HOH 0 mi W1V13H
0 £S"92 00 •ι 90 12 ΐίΖ'Ζ- W6 5 HOH 0 9 W1V13H0 £ S "92 00 • ι 90 12 ΐίΖ'Ζ- W6 5 HOH 0 9 W1V13H
0 09'1£ 00 •ι οο'ει- 622*8 88 £AS HOH 0 s W1V13H0 09'1 £ 00 • ι οο'ει- 622 * 8 88 £ AS HOH 0 s W1V13H
0 Z6"SZ 00 "I £9'6l m'Li- S06"2f 2 9 HOH 0 N1V13H0 Z6 "SZ 00" I £ 9'6l m'Li-S06 "2f 2 9 HOH 0 N1V13H
0 E8"82 00 Ί Ζ99'91 028 '02 I S HOH 0 mi 丄 V丄ョ H0 E8 "82 00 Ί Ζ99'91 028 '02 I S HOH 0 mi 丄 V 丄 H
0 8に 9£ 00 'L ·91- οεζ-ε- 8L8'0 0Z9 HOH 0 H1V13H0 8 to 9 £ 00 'L91-οεζ-ε- 8L8'0 0Z9 HOH 0 H1V13H
0 ·εε 00 Ί 9Z9-U- sorzt' 699 HOH 0 W1V13H0εε 00 Ί 9Z9-U- sorzt '699 HOH 0 W1V13H
0 22 '81 00 "L 190'9- £Ζ8·8 899 HOH 0 o H1V13H0 22 '81 00 "L 190'9- £ Ζ8.8 899 HOH 0 o H1V13H
0 ε6·εε 00 •1 S68 L- 89*^2 99L '£9 Z9S HOH 0 6£8Z W1V13H0 ε6 ・ εε 00 • 1 S68 L- 89 * ^ 2 99L '£ 9 Z9S HOH 0 6 £ 8Z W1V13H
0 96 "82 00 •1 16S.II- 282 '62 992 'οε 999 HOH 0 8£82 H1V13H0 96 "82 00 • 1 16S.II- 282 '62 992 'οε 999 HOH 0 8 £ 82 H1V13H
0 19 "ζε 00 Ί Ε29Ί- 888"8l 999 HOH 0 U2L 丄ョ H0 19 "ζε 00 Ί Ε29Ί-888" 8l 999 HOH 0 U2L
0 00 '！ 9tO'9l £8f "02 ^99 HOH 0 9£8i WIV13H0 00 '! 9tO'9l £ 8f "02 ^ 99 HOH 0 9 £ 8i WIV13H
0 ΟΙ'Π 00' Ί '8 200'91- 99Π- £99 HOH 0 9£8i WIV13H0 ΟΙ'Π 00 'Ί' 8 200'91- 99Π- £ 99 HOH 0 9 £ 8i WIV13H
0 6 ·81 00 1 6£2Ό- εοε'6- 6Z0'8t? HOH 0 W1V13H0 6 · 81 00 1 6 £ 2Ό- εοε'6- 6Z0'8t? HOH 0 W1V13H
0 09·εζ 00' Ί 90"£ οιε .ι 192*6 L99 HOH 0 W1V13H0 09 · εζ 00 'Ί 90 "£ οιε .ι 192 * 6 L99 HOH 0 W1V13H
0 f9'iL οο■ ■1 999"1- 92 '9 丄 6 8 099 HOH 0 ZZ2L H1V13H0 f9'iL οο ■ 1 999 "1- 92 '9 丄 6 8 099 HOH 0 ZZ2L H1V13H
0 0£'6L 00' Ί 9SL 71 9·1 - £ ·6 699 HOH 0 mi HiVi3H0 0 £ '6L 00' Ί 9SL 71 9.1-£ 6 699 HOH 0 mi HiVi3H
0 £2 '61 00' Ί £86"£- 19Γ91 9Z8 S 8S9 HOH 0 0E8I W1V13H0 £ 2 '61 00 '86 £ 86 "£ -19Γ91 9Z8 S 8S9 HOH 0 0E8I W1V13H
0 6072 00' ■1 28Ζ*9 ιιο'οι— 806*01 I9S HOH 0 W1V13H0 6072 00 '■ 1 28Ζ * 9 ιιο'οι— 806 * 01 I9S HOH 0 W1V13H
0 9Γ92 00' 1 £6 ·91 I19'LL 999 HOH 0 H1V13H0 9Γ92 00 '1 £ 691 I19'LL 999 HOH 0 H1V13H
0 ΰΡΉ 00' 'ι 019"9 969 Ό 869 '8 S99 HOH 0 LZ L H1V13H0 ΰΡΉ 00 '' ι 019 "9 969 Ό 869 '8 S99 HOH 0 LZ L H1V13H
0 00' Ί m'z- 809 "6£ 919*18 MS HOH 0 i W1V13H0 00 'Ί m'z- 809 "6 £ 919 * 18 MS HOH 0 i W1V13H
0 69"6L 00' Ί 288"6L 98ε ·ει E99 HOH 0 H1V13H0 69 "6L 00 'Ί 288" 6L 98ε · ει E99 HOH 0 H1V13H
0 6£'6£ 00' Ί 6£ 'οζ- 6SZ"9- 9if Έ9 299 HOH 0 mL H1V13H0 6 £ '6 £ 00' Ί 6 £ 'οζ-6SZ "9-9if Έ9 299 HOH 0 mL H1V13H
0 6 Ή 00' Ί ΖΖ^'ΖΖ- 680 193 HOH 0 WiViaH0 6 Ή 00 'ΖΖ ΖΖ ^' ΖΖ- 680 193 HOH 0 WiViaH
0 SZ'ZZ 00' Ί ·ε S6£'9l- 822 "8 09S HOH 0 im W1V13H0 SZ'ZZ 00 'εεS6 £' 9l- 822 "8 09S HOH 0 im W1V13H
0 89 ε 00' Ί E69't7 999*91- 008 Ί9 HOH 0 \m H1V1HH0 89 ε 00 'Ί E69't7 999 * 91- 008 Ί9 HOH 0 \ m H1V1HH
0 QZ'H 00' Ί 99L 1 668*92 962.19 m HOH 0 un隨丄ョ H0 QZ'H 00 'Ί 99L 1 668 * 92 962.19 m HOH 0 un
0 6"9Ζ 00' L 00 I 921'1L £6·9 i HOH 0 618丄 W1V13H0 6 "9Ζ 00 'L 00 I 921'1L £ 6.9i HOH 0 618 丄 W1V13H
0 62 "92 00' 1 296*61 9 W0 - 1 ' IS 9 S HOH 0 818Z W1V13H0 62 "92 00 '1 296 * 61 9 W0-1' IS 9 S HOH 0 818Z W1V13H
0 8 ·61 00' Ί 208"0L nrsi- UZ'l- HOH 0 i W1V13H0 8 61 00 'Ί 208 "0L nrsi- UZ'l- HOH 0 i W1V13H
0 8 S2 00' Ί 919"£L- 29丄 ·91- HOH 0 9L8Z H1V13H 0 8 S2 00 'Ί 919 "£ L- 29 丄 91-HOH 0 9L8Z H1V13H
(0 0)^)乙拏 £.600/COO∑df/X3d 表 7(その 41) (0 0) ^) Halla £ .600 / COO∑df / X3d Table 7 (Part 41)
HETATM 7849 0 HOH 577 26.942 7.743 1.00 28.85 0HETATM 7849 0 HOH 577 26.942 7.743 1.00 28.85 0
HETATM 7850 0 HOH 578 71.869 -10.618 8.150 1.00 27.85 0HETATM 7850 0 HOH 578 71.869 -10.618 8.150 1.00 27.85 0
HETATM 7851 0 HOH 579 57.904 -23.191 6.377 1.00 34.71 0HETATM 7851 0 HOH 579 57.904 -23.191 6.377 1.00 34.71 0
HETATM 7852 0 HOH 580 9.458 5.764 17.295 1.00 39.46 0HETATM 7852 0 HOH 580 9.458 5.764 17.295 1.00 39.46 0
HETATM 7853 0 HOH 581 2.643 -12.576 -13.743 1.00 27.04 0HETATM 7853 0 HOH 581 2.643 -12.576 -13.743 1.00 27.04 0
HETATM 7854 0 HOH 582 56.165 18.356 -10.583 1.00 25.59 0HETATM 7854 0 HOH 582 56.165 18.356 -10.583 1.00 25.59 0
HETATM 7855 0 HOH 583 47.399 18.511 10.215 1.00 15.00 0HETATM 7855 0 HOH 583 47.399 18.511 10.215 1.00 15.00 0
HETATM 7856 0 HOH 584 20.832 30.338 7.497 1.00 35.07 0HETATM 7856 0 HOH 584 20.832 30.338 7.497 1.00 35.07 0
HETATM .7857 0 HOH 585 45.217 -9.122 0.044 1.00 21.83 0HETATM .7857 0 HOH 585 45.217 -9.122 0.044 1.00 21.83 0
HETATM 7858 0 HOH 586 2.254 22.065 15.706 1.00 30.93 0HETATM 7858 0 HOH 586 2.254 22.065 15.706 1.00 30.93 0
HETATM 7859 0 HOH 587 18.710 1.044 5.506 1.00 30.95 0HETATM 7859 0 HOH 587 18.710 1.044 5.506 1.00 30.95 0
HETATM 7860 0 HOH 588 14.892 -25.695 -8.772 1.00 24.58 0HETATM 7860 0 HOH 588 14.892 -25.695 -8.772 1.00 24.58 0
HETATM 7861 0 HOH 589 12.043 -9.421 -10.370 1.00 28.76 0HETATM 7861 0 HOH 589 12.043 -9.421 -10.370 1.00 28.76 0
HETATM 7862 0 HOH 590 -1.851 33.789 -7.187 1.00 23.62 0HETATM 7862 0 HOH 590 -1.851 33.789 -7.187 1.00 23.62 0
HETATM 7863 0 HOH 591 9.571 -18.540 -18.256 1.00 36.88 0HETATM 7863 0 HOH 591 9.571 -18.540 -18.256 1.00 36.88 0
HETATM 7864 0 HOH 592 59.818 -14.083 18.348 1.00 34.45 0HETATM 7864 0 HOH 592 59.818 -14.083 18.348 1.00 34.45 0
HETATM 7865 0 HOH 593 4.090 6.418 12.579 1.00 31.65 0HETATM 7865 0 HOH 593 4.090 6.418 12.579 1.00 31.65 0
HETATM 7866 0 HOH 594 39.375 -2.619 5.753 1.00 28.05 0HETATM 7866 0 HOH 594 39.375 -2.619 5.753 1.00 28.05 0
HETATM 7867 0 HOH 595 -1.681 -0.195 -18.225 1.00 39.54 0HETATM 7867 0 HOH 595 -1.681 -0.195 -18.225 1.00 39.54 0
HETATM 7868 0 HOH 596 32.706 -20.829 -2.207 1.00 33.43 0HETATM 7868 0 HOH 596 32.706 -20.829 -2.207 1.00 33.43 0
HETATM 7869 0 HOH 597 48.154 15.398 -4.574 1.00 31.43 0HETATM 7869 0 HOH 597 48.154 15.398 -4.574 1.00 31.43 0
HETATM 7870 0 HOH 598 10.062 24.859 -19.033 1.00 17.99 0HETATM 7870 0 HOH 598 10.062 24.859 -19.033 1.00 17.99 0
HETATM 7871 0 HOH 599 27.810 30.771 -10.601 1.00 35.22 0HETATM 7871 0 HOH 599 27.810 30.771 -10.601 1.00 35.22 0
HETATM 7872 0 HOH 600 20.987 19.830 8.262 1.00 34.74 0HETATM 7872 0 HOH 600 20.987 19.830 8.262 1.00 34.74 0
HETATM 7873 0 HOH 601 5.391 28.851 - 8.338 1.00 24.65 0HETATM 7873 0 HOH 601 5.391 28.851-8.338 1.00 24.65 0
HETATM 7874 0 HOH 602 38.063 -5.526 2.718 1.00 27.21 0HETATM 7874 0 HOH 602 38.063 -5.526 2.718 1.00 27.21 0
HETATM 7875 0 HOH 603 45.710 -9.377 21.226 1.00 34.08 0HETATM 7875 0 HOH 603 45.710 -9.377 21.226 1.00 34.08 0
HETATM 7876 0 HOH 604 -6.385 7.144 4.547 1.00 25.79 0HETATM 7876 0 HOH 604 -6.385 7.144 4.547 1.00 25.79 0
HETATM 7877 0 HOH 605 63.743 29.416 3.615 1.00 36.15 0HETATM 7877 0 HOH 605 63.743 29.416 3.615 1.00 36.15 0
HETATM 7878 0 HOH 606 50.017 5.442 -4.005 1.00 32.85 0HETATM 7878 0 HOH 606 50.017 5.442 -4.005 1.00 32.85 0
HETATM 7879 0 HOH 607 67.894 4.837 1.00 29.50 0HETATM 7879 0 HOH 607 67.894 4.837 1.00 29.50 0
HETATM 7880 0 HOH 608 17.225 19.612 -15.145 1.00 30·'2·1 0HETATM 7880 0 HOH 608 17.225 19.612 -15.145 1.00 30
HETATM 7881 0 HOH 609 28.572 22.202 1.633 1.00 28.95 0 46 表 7 (その 42) HETATM 7881 0 HOH 609 28.572 22.202 1.633 1.00 28.95 0 46 Table 7 (Part 42)
HETATM 7882 0 61.321 10.231 -18.212 1.00 26.79 0 HETATM 7883 0 -9.797 -4.665 -6.653 1.00 28.61 0HETATM 7882 0 61.321 10.231 -18.212 1.00 26.79 0 HETATM 7883 0 -9.797 -4.665 -6.653 1.00 28.61 0
HHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHH HETATM 7884 0 oooooooooooooo oooooooooooooooooooHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHH 15.490 23.890 -20.757 1.00 44.30 0 HETATM 7885 0 12.480 1.895 7.173 1.00 17.24 0  HHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHH HETATM 7884 0 oooooooooooooo oooooooooooooooooooooHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHH 15.490 23.890 7.0.7 17.07 24.890 17.07 17.57 14.000 17.07 7.890 17.80 -0.70 7.48 7.000 17.07 7.480 17.07 7.890 17.07 17.57 14.000 17.07 7.480 17.07 17.90 7.48 17.07 7.890 17.07 17.57 14.000 7.07 7.480 17.07 7.890 7.07 17.57 1.790 17.07 17.480 7.07 7.800 7.07 7.890 17.07 17.57 7.790 7.480 17.071.
66666666666 66666666666666666666644433322222223333332223 1 - 111111111  66666666666 66666666666666666666644433322222223333332223 1-111111111
HETATM 7886 0 o o41 o 472 o6846789 o 256 o 92392353 ·t5 - - Ϊ I 11 29.358 27.188 -12.296 1.00 30.06 0 HETATM 7887 0 1.642 -11.594 -11.651 1.00 22.45 0 HETATM 7888 0 47.016 20.117 -14.468 1.00 24.77 0 HETATM 7889 0 43.613 15.956 -6.852 1.00 26.98 0 HETATM 7890 0 47.974 13.499 -6.185 1.00 25.64 0 HETATM 7891 0 31.529 -11.722 11.732 1.00 34.01 0 HETATM 7892 0 47.339 46.118 13.303 1.00 32.70 0 HETATM 7893 0 9.107 13.592 6.913 1.00 27.03 0 HETATM 7894 0 -8.219 14.538 -14.309 1.00 29.51 0 HETATM 7895 0 51.973 0.491 -17.922 1.00 35.13 0 HETATM 7896 0 -8.837 -2.571 -4.934 1.00 37.19 0 HETATM 7897 0 34.136 -15.151 11.187 1.00 28.79 0 HETATM 7898 0 -1.314 18.473 12.850 1.00 34.28 0 HETATM 7899 0 16.910 36.872 -3.432 1.00 28.70 0 HETATM 7900 0 40.248 0.801 -5.311 1.00 22.40 0 HETATM 7901 0 32.481 -2.425 -5.772 1.00 42.39 0 HETATM 7902 0 18.826 22.732 -3.253 1.00 30.67 0 HETATM 7903 0 47.497 -14.494 -14.830 1.00 36.18 0 HETATM 7904 0 -11.036 -8.552 9.634 1.00 23.43 0 HETATM 7905 0 22.308 28.257 8.368 1.00 26.38 0 HETATM 7906 0 24.692 - 9.545 1.178 1.00 23.31 0 HETATM 7907 0 65.254 26.778 -7.797 1.00 35.67 0 HETATM 7908 0 14.094 1.141 3.122 1.00 20.18 0 HETATM 7909 0 11.628 8.008 -6.316 1.00 24.94 0 HETATM 7910 0 5.756 17.105 -12.893 1.00 28.56 0 HETATM 7911 0 9.933 27.861 -18.344 1.00 16.88 0 HETATM 7912 0 5.396 29.308 -22.134 1.00 38.04 0 HETATM 7913 0 20.325 22.148 -1.176 1.00 21.21 0 HETATM 7914 0 9.482 -2.191 -8.862 1.00 32.78 0 0 6·Μ 00 "l 9S6 998 ΌΙ 0927 9 9 ■ 0 i H1V13HHETATM 7886 0 o o41 o 472 o6846789 o 256 o 92392353 43.613 15.956 -6.852 1.00 26.98 0 HETATM 7890 0 47.974 13.499 -6.185 1.00 25.64 0 HETATM 7891 0 31.529 -11.722 11.732 1.00 34.01 0 HETATM 7892 0 47.339 46.118 13.303 1.00 32.70 0 HETATM 7893 0 9.107 13.592 6.913 1.00 27.03 0 HETA7 14.538 -14.309 1.00 29.51 0 HETATM 7895 0 51.973 0.491 -17.922 1.00 35.13 0 HETATM 7896 0 -8.837 -2.571 -4.934 1.00 37.19 0 HETATM 7897 0 34.136 -15.151 11.187 1.00 28.79 0 HETATM 7898 0 -1.314 18.473 12.850 1.00 34.28 0 HETA 0 16.910 36.872 -3.432 1.00 28.70 0 HETATM 7900 0 40.248 0.801 -5.311 1.00 22.40 0 HETATM 7901 0 32.481 -2.425 -5.772 1.00 42.39 0 HETATM 7902 0 18.826 22.732 -3.253 1.00 30.67 0 HETATM 7903 0 47.497 -14.494 -14.830 1.00 36.18 HETATM 7904 0 -11.036 -8.552 9.634 1.00 23.43 0 HETATM 7905 0 22.308 28.257 8.368 1.00 26.38 0 HETATM 7906 0 24.692-9.545 1.178 1.00 23.31 0 HETATM 7907 0 65.254 26.778 -7.797 1.00 35.67 0 HETATM 7908 0 14.094 1.141 3.122 1.00 20.18 0 HETATM 7909 0 11.628 8.008 -6.316 1.00 24.94 0 HETATM 7910 02.893.105 17.105 1.00 28.56 0 HETATM 7911 0 9.933 27.861 -18.344 1.00 16.88 0 HETATM 7912 0 5.396 29.308 -22.134 1.00 38.04 0 HETATM 7913 0 20.325 22.148 -1.176 1.00 21.21 0 HETATM 7914 0 9.482 -2.191 -8.862 1.00 32.78 0 0 6Μ 00 "l 9S6 998 ΌΙ 0927 9 9 ■ 0 i H1V13H
0 96 £ 00 ■I S£8'8- LlO'lZ HOH 0 9 6 H1V13H0 96 £ 00 ■ I S £ 8'8- LlO'lZ HOH 0 9 6 H1V13H
0 LL'Zl 00 Ί 6ff "Sl- loroi- 8ZL 9 HOH 0 W1V13H0 LL'Zl 00 Ί 6ff "Sl-loroi-8ZL 9 HOH 0 W1V13H
0 t7'lE 00 "I 88 Ί ^98*0- Z 9 HOH 0 丄 W1V13H0 t7'lE 00 "I 88 Ί ^ 98 * 0- Z 9 HOH 0 丄 W1V13H
0 96'9£ 00 •I 2L£ '9- 6^671- 'sz 9 HOH 0 H1V13H0 96'9 £ 00I2L £ '9- 6 ^ 671-'sz 9 HOH 0 H1V13H
0 19"2£ 00 •I U9 •0 696 ΌΙ 0Z9 HOH 0 6 H1V13H0 19 "2 £ 00 • I U9 • 0 696 ΌΙ 0Z9 HOH 0 6 H1V13H
0 00 Ί ■ε- 62S "81 126 "£t7 699 HOH 0 6Z W1V13H0 00 Ί ■ ε-62S "81 126" £ t7 699 HOH 0 6Z W1V13H
0 zriz 00 ,1 9£6 •0 9Ζ6"61 m' 899 HOH 0 H1V13H0 zriz 00, 1 9 £ 6 • 0 9Ζ6 "61 m '899 HOH 0 H1V13H
0 00 '9 00' Ί Z92 •ει 8 ·11- 199 HOH 0 6£6i W1V13H0 00 '9 00' Ί Z92 • ει 811-199 HOH 0 6 £ 6i W1V13H
0 S8'W 00 ,1 ILZ •9- 99t7'8L 699*11- 999 HOH 0 8£6i W1V13H0 S8'W 00, 1 ILZ9- 99t7'8L 699 * 11- 999 HOH 0 8 £ 6i W1V13H
0 '9£ 00' 'I 9ZZ •61- 1^28 '02 899 L 999 HOH 0 i£6i H1V13H0 '9 £ 00' 'I 9ZZ61-1 ^ 28 '02 899 L 999 HOH 0 i £ 6i H1V13H
0 £9"0£ 00' Ί 2E9 •ει fl8"9£ 902*6 99 HOH 0 9E6 W1V1HH0 £ 9 "0 £ 00 'Ί 2E9 • ει fl8" 9 £ 902 * 6 99 HOH 0 9E6 W1V1HH
0 20'8£ 00' 'I 68 ■ει 818'9L £99 HOH 0 W1V13H0 20'8 £ 00 '' I 68 ■ ει 818'9L £ 99 HOH 0 W1V13H
0 99'9Z 00' ■I 28Γ2- ιιη 92 299 HOH 0 L H1V13H0 99'9Z 00 'I 28Γ2- ιιη 92 299 HOH 0 L H1V13H
0 26*61 00' 'I οεο ■21 - £89'l £927- 199 HOH 0 W1V1HH0 26 * 61 00 '' I οεο 21-£ 89'l £ 927- 199 HOH 0 W1V1HH
0 0 '82 00' Ί 996 "91 9Ζ9 1- 099 HOH 0 Z£6 W1V13H0 0 '82 00 'Ί 996 "91 9Ζ9 1- 099 HOH 0 Z £ 6 W1V13H
0 80.62 00' Ί m ■0 699 HOH 0 L£6I H1V13H0 80.62 00 'Ί m ■ 0 699 HOH 0 L £ 6I H1V13H
0 00 "S£ 00' 'I 2S ' 21- 18 ·ζε 69Ζ·6 999 HOH 0 0£6Z W1V13H0 00 "S £ 00 '' I 2S '21-18 ζε 69Ζ 6 999 HOH 0 0 £ 6Z W1V13H
0 66 "2£ 00' Ί ΙΙ 91 9i6"0L 199 HOH 0 626 W1V13H0 66 "2 £ 00 'Ί ΙΙ 91 9i6" 0L 199 HOH 0 626 W1V13H
0 99'£2 00' Ί ISO ■ε ε ' - 266-02 9S9 HOH 0 8262 W1V13H0 99 '£ 2 00' Ί ISO ■ ε ε '-266-02 9S9 HOH 0 8262 W1V13H
0 U'2£ 00' 'I 612*6 999 HOH 0 LZQL IN丄 V丄ョ H0 U'2 £ 00 '' I 612 * 6 999 HOH 0 LZQL IN 丄 V 丄 H
0 Z9*0£ 00' Ί 0 2 nri- S92.9S frS9 HOH 0 9Z62 W1V13H0 Z9 * 0 £ 00 'Ί 0 2 nri- S92.9S frS9 HOH 0 9Z62 W1V13H
0 00' Ί 066 t^89"0l E99 HOH 0 926Z W1V13H0 00 'Ί 066 t ^ 89 "0l E99 HOH 0 926Z W1V13H
0 29*92 00' Ί 80 £9 S- 2S9 HOH 0 PZ6L W1V13H0 29 * 92 00 'Ί 80 £ 9 S-2S9 HOH 0 PZ6L W1V13H
0 09'2£ 00' Ί Z9£ L99 HOH 0 ZZGL H1V13H0 09'2 £ 00 'Ί Z9 £ L99 HOH 0 ZZGL H1V13H
0 20 "82 00' 'I 882 'τ - 81S"S- 6L9'82 0S9 HOH 0 ZZSL W1V13H0 20 "82 00 '' I 882 'τ-81S" S-6L9'82 0S9 HOH 0 ZZSL W1V13H
0 9 0 00' l 99Γ9- 8Lに 61 999 '92 HOH 0 IZ8L W1V13H0 9 0 00 'l 99Γ9-8L 61 999 '92 HOH 0 IZ8L W1V13H
0 9 ·οε 00' Ί 82£'0L 08 Ί- 818. HOH 0 026 W丄 V丄ョ H0 9 · οε 00 'Ί 82 £' 0L 08 Ί- 818. HOH 0 026 W 丄 V 丄 H
0 U'22 00' Ί £92 ■ο- 999"9£ HOH 0 616丄 W1V13H0 U'22 00 'Ί £ 92 ■ ο- 999 "9 £ HOH 0 616 丄 W1V13H
0 89 ' Z 00' 'I Z O'S ZS9'S- εεε ε 9^9 HOH 0 816Z W1V13H0 89 'Z 00' 'I Z O'S ZS9'S- εεε ε9 ^ 9 HOH 0 816Z W1V13H
0 L9'H 00' Ί 81Π 9L2'9 HOH 0 1L6 H1V13H0 L9'H 00 'Ί 81Π 9L2'9 HOH 0 1L6 H1V13H
0 IQ' 00' Ί z '9 990.2 IU' - HOH 0 916Z W1V13H0 IQ '00' Ί z '9 990.2 IU'-HOH 0 916Z W1V13H
0 00' Ί 26Γ0 9S6"£ nv% m HOH 0 916Z H1V13H 0 00 'Ί 26Γ0 9S6 "£ nv% m HOH 0 916Z H1V13H
L TL T
S L600/£00Zdi/Ud 1" £ΪΟ/1"ΟΟ OAV 表 7 (その 44) S L600 / £ 00Zdi / Ud 1 "£ ΪΟ / 1" ΟΟ OAV Table 7 (Part 44)
HETATM 7948 0 HOH 676 52.623 -21.796 -4.375 1 .00 28.41 0HETATM 7948 0 HOH 676 52.623 -21.796 -4.375 1 .00 28.41 0
HETATM 7949 0 HOH 677 29.686 33.391 8.561 1 .00 36.79 0HETATM 7949 0 HOH 677 29.686 33.391 8.561 1 .00 36.79 0
HETATM 7950 0 HOH 678 34.768 -10.973 1, .00 36.13 0HETATM 7950 0 HOH 678 34.768 -10.973 1, .00 36.13 0
HETATM 7951 0 HOH 679 10.068 11.800 4.118 1 .00 33.72 0HETATM 7951 0 HOH 679 10.068 11.800 4.118 1 .00 33.72 0
HETATM 7952 0 HOH 680 11.997 23.146 -20.518 1, .00 31.78 0HETATM 7952 0 HOH 680 11.997 23.146 -20.518 1, .00 31.78 0
HETATM 7953 0 HOH 681 14.817 -24.066 -11.114 1, .00 32.58 0HETATM 7953 0 HOH 681 14.817 -24.066 -11.114 1, .00 32.58 0
HETATM 7954 0 HOH 682 60.945 40.887 11.318 1, .00 29.03 0HETATM 7954 0 HOH 682 60.945 40.887 11.318 1, .00 29.03 0
HETATM 7955 0 HOH 683 44.219 20.370 -10.659 1, .00 29.25 0HETATM 7955 0 HOH 683 44.219 20.370 -10.659 1, .00 29.25 0
HETATM 7956 0 HOH 684 5.166 -13.086 23.591 1, .00 24.14 0HETATM 7956 0 HOH 684 5.166 -13.086 23.591 1, .00 24.14 0
HETATM 7957 0 HOH 685 14.648 -1.067 -1.029 1, .00 37.17 0HETATM 7957 0 HOH 685 14.648 -1.067 -1.029 1, .00 37.17 0
HETATM 7958 0 HOH 686 68.114 24.630 6.276 1, .00 30.46 0HETATM 7958 0 HOH 686 68.114 24.630 6.276 1, .00 30.46 0
HETATM 7959 0 HOH 687 -13.935 25.483 0.346 1, .00 42.20 0HETATM 7959 0 HOH 687 -13.935 25.483 0.346 1, .00 42.20 0
HETATM 7960 0 HOH 688 68.402 -0.596 8.924 1, .00 30.15 0HETATM 7960 0 HOH 688 68.402 -0.596 8.924 1, .00 30.15 0
HETATM 7961 0 HOH 689 58.316 -0.122 15.162 1, .00 21.00 0HETATM 7961 0 HOH 689 58.316 -0.122 15.162 1, .00 21.00 0
HETATM 7962 0 HOH 690 -0.070 35.056 16.014 1, .00 39.34 0HETATM 7962 0 HOH 690 -0.070 35.056 16.014 1, .00 39.34 0
HETATM 7963 0 HOH 691 53.348 17.892 22.219 1. .00 35.30 0HETATM 7963 0 HOH 691 53.348 17.892 22.219 1. .00 35.30 0
HETATM 7964 0 HOH 692 -6.739 -6.935 16.707 1, .00 29.92 0HETATM 7964 0 HOH 692 -6.739 -6.935 16.707 1, .00 29.92 0
HETATM 7965 0 HOH 693 34.071 -7.293 3.262 1. .00 31.10 0HETATM 7965 0 HOH 693 34.071 -7.293 3.262 1. .00 31.10 0
HETATM 7966 0 HOH 694 10.800 13.579 2.432 1. .00 26.96 0HETATM 7966 0 HOH 694 10.800 13.579 2.432 1. .00 26.96 0
HETATM 7967 0 HOH 695 8.441 8.874 6.258 1. .00 44.85 0HETATM 7967 0 HOH 695 8.441 8.874 6.258 1. .00 44.85 0
HETATM 7968 0 HOH 696 -5.036 -3.204 -19.512 1. .00 31.58 0HETATM 7968 0 HOH 696 -5.036 -3.204 -19.512 1. .00 31.58 0
HETATM 7969 0 HOH 697 15.990 -7.563 -8.071 1. .00 23.11 0HETATM 7969 0 HOH 697 15.990 -7.563 -8.071 1. .00 23.11 0
HETATM 7970 0 HOH 698 13.201 -3.973 1. ,00 18.32 0HETATM 7970 0 HOH 698 13.201 -3.973 1., 00 18.32 0
HETATM 7971 0 HOH 699 40.734 33.440 14.895 1. .00 26.93 0HETATM 7971 0 HOH 699 40.734 33.440 14.895 1. .00 26.93 0
HETATM 7972 0 HOH 700 -9.183 -2.073 10.706 1. ,00 22.73 0HETATM 7972 0 HOH 700 -9.183 -2.073 10.706 1., 00 22.73 0
HP丁 A丁 M 7973 o HOH 701 57.538 25.839 11.520 1. , 00 28.65 oHP D A D M 7973 o HOH 701 57.538 25.839 11.520 1., 00 28.65 o
HETATM 7974 0 HOH 702 8.541 0.154 22.310 1. ,00 21.84 0HETATM 7974 0 HOH 702 8.541 0.154 22.310 1., 00 21.84 0
HETATM 7975 0 HOH 703 2.628 6.186 -22.448 1. 00 28.71 0HETATM 7975 0 HOH 703 2.628 6.186 -22.448 1.00 28.71 0
HETATM 7976 0 HOH 704 5.965 8.734 21.179 1. 00 35.14 0HETATM 7976 0 HOH 704 5.965 8.734 21.179 1.00 35.14 0
HETATM 7977 0 HOH 705 59.458 -3.204 -19.659 1. 00 22.63 0HETATM 7977 0 HOH 705 59.458 -3.204 -19.659 1.00 22.63 0
HETATM 7978 0 HOH 706 16.286 -5.239 -9.402 1. 00 27.71 0HETATM 7978 0 HOH 706 16.286 -5.239 -9.402 1.00 27.71 0
HETATM 7979 0 HOH 707 13.237 11.512 1.929 1. 00 41.66 0HETATM 7979 0 HOH 707 13.237 11.512 1.929 1.00 41.66 0
HETATM 7980 0 HOH 708 20.135 -11.276 1. 00 36.22 0 49 表 7 (その 45) HETATM 7980 0 HOH 708 20.135 -11.276 1.00 36.22 0 49 Table 7 (Part 45)
HETATM 7981 0 HOH 709 -10.517 28.830 -12.779 1. ,00 34.01 0HETATM 7981 0 HOH 709 -10.517 28.830 -12.779 1., 00 34.01 0
HETATM 7982 0 HOH 710 3.142 36.832 -10. 042 1. .00 34.10 0HETATM 7982 0 HOH 710 3.142 36.832 -10. 042 1. .00 34.10 0
HETATM 7983 0 HOH 711 29.727 -4.781 6. 680 1. .00 36.64 0HETATM 7983 0 HOH 711 29.727 -4.781 6.680 1. .00 36.64 0
HETATM 7984 0 HOH 712 6.692 -13.850 -14. 741 1. ,00 32.57 0HETATM 7984 0 HOH 712 6.692 -13.850 -14. 741 1., 00 32.57 0
HETATM 7985 0 HOH 713 16.233 -6.587 -11. 574 1, .00 40.68 0HETATM 7985 0 HOH 713 16.233 -6.587 -11. 574 1, .00 40.68 0
HETATM 7986 0 HOH 714 15.483 17.178 0. 390 1. .00 31.22 0 END HETATM 7986 0 HOH 714 15.483 17.178 0.390 1. .00 31.22 0 END
N 8·81 00 II '8 Ι soo's V09 V OiJd N 隱 VN 8 81 00 II '8 Ι soo's V09 V OiJd N Oki V
0 9£ ·81 00 •I 69Ε t^ 9 "9 09 V AID 0 ε 隱 V0 9 £ · 81 00 • I 69Ε t ^ 9 "9 09 V AID 0ε o
3 99'8L 00 •I 9εε'8 8 •21 09 V 人" 13 3 ZLl 隱 V 3 99'8L 00 • I 9εε'8 8 • 21 09 V person ”13 3 ZLl Hiding V
οε·8ΐ 00 ■I 210'6 192 •ει εε 's 09 V 人 Ί3 3 IZE 隱 V οε · 8ΐ 00 ■ I 210'6 192 • ει εε 's 09 V People Ί3 3 IZE Oki V
N U '81 00 "l 862 '8 £88· 9L0*9 09 V λ!3 N οζε 隠 VN U '81 00 "l 862 '8 £ 889L0 * 9 09 V λ! 3 N οζε Hidden V
0 96"6L 00 •i 98L '01 000 ■91 129'9 69 V 1VA 0 69ε 隱 V0 96 "6L 00 • i 98L '01 000 ■ 91 129'9 69 V 1VA 0 69ε Oki V
0 £ '81 00 Ί 896*8 126 '91 S "9 69 V 1VA 3 89ε 隱 V0 £ '81 00 Ί 896 * 8 126 '91 S "9 69 V 1VA 3 89ε Hidden V
3 EL 71 00 •I 996 'i •81 £86 ^ 69 V 1VA 隱 V 3 EL 71 00 • I 996 'i • 81 £ 86 ^ 69 V 1VA Oki V
89"9l 00 'I £t?9 •6L Oil " 69 V 1VA 99ε 隠 V 89 "9l 00 'I £ t? 9 • 6L Oil" 69 V 1VA 99ε Hidden V
3 09'iL 00 Ί 009-8 99£ ■81 10 ' 9 69 V 1VA 93 隱 V3 09'iL 00 Ί 009-8 99 £ ■ 81 10 '9 69 V 1VA 93 Oki V
0 69'il 00 ,1 ■Zl 6LI '2 69 V "1VA V3 m I/I101V0 69'il 00, 1Zl 6LI '2 69 V "1VA V3 m I / I101V
N ZS 1 00 Ί 089-9 9£8 •91 8807 69 V I A N ε9ε 隱 VN ZS 1 00 Ί 089-9 9 £ 8 • 91 8807 69 V I A N ε9ε Oki V
0 £971 00 •L £9f '9 ISO 1 6ΐε·6 89 V SAD 0 隱 V0 £ 971 00 • L £ 9f '9 ISO 16ΐε6 89 V SAD 0 Hidden V
3 9Z" L 00 •I 996*9 £Z8 '91 02·8 89 V SAO 0 19£ INOIV3 9Z "L 00 • I 996 * 9 £ Z8 '91 02 · 8 89 V SAO 0 19 £ INOIV
S 92*81 00 Ί £66'l 910 •81 9 Γ8 89 V SAO 3S 09ε 隱 VS 92 * 81 00 Ί £ 66'l 910 • 81 9 Γ8 89 V SAO 3S 09ε Oki V
3 E67L 00 'I 290 •81 16' 89 V SAO ao 69£ W01V3 E67L 00 'I 290 • 81 16' 89 V SAO ao 69 £ W01V
0 OVLl 00' ■I 09f ^ 169 "9L 89 V SAD o 8S£ W01V0 OVLl 00 '■ I 09f ^ 169 "9L 89 V SAD o 8S £ W01V
N 6071 00 •I 091 m •SL "8·9 89 V SAO N 9£ W01VN 6071 00 • I 091 m • SL "8.989 V SAO N 9 £ W01V
0 92"9L 00' Ί 086 'ει 268'丄 19 V SIH 0 99£ 瞧 V0 92 "9L 00 'Ί 086' ει 268 '丄 19 V SIH 0 99 £ 瞧 V
3 91 00' ■I 919 'PI 968·9 i V SIH D 99£ 隱 V3 91 00 '■ I 919' PI 9689 i V SIH D 99 £ Hidden V
N 60 l 00 Ί ΖΖΖΌ 'L 19 V SIH z S£ W01VN 60 l 00 Ί ΖΖΖΌ 'L 19 V SIH z S £ W01V
3 00' Ί 6££'0- ££S ' 1 1789 "9 i9 V SIH £98 W01V3 00 'Ί 6 ££' 0- ££ S '1 1789 "9 i9 V SIH £ 98 W01V
N LVPl 00' ■I 109 "0 900 ^1 918'S ZS V SIH ION 2S£ WOiVN LVPl 00 '■ I 109 "0 900 ^ 1 918'S ZS V SIH ION 2S £ WOiV
D 8 'εΐ 00' Ί 996 III' I 19 V SIH ZQ LS£ 隱 VD 8 'εΐ 00' Ί 996 III 'I 19 V SIH ZQ LS £
3 6£· 00' Ί 099'L 2£9 ■ει Z9 V SIH 33 09£ H01V3 6 £ 00 'Ί 099'L 2 £ 9 ■ ει Z9 V SIH 33 09 £ H01V
3 96· 00' ,1 2087 996 Z9 V SIH 93 6^2 W01V3 9600 ', 1 2087 996 Z9 V SIH 93 6 ^ 2 W01V
0 99"9L 00' Ί ££8 'EL 809 '9
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V SIH V3 m 隱 V0 99 "9L 00 'Ί ££ 8' EL 809 '9
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V SIH V3 m Oki V
N t?Z'9l 00' Ί ζε6·ε IL Z9 V SIH N 隱 VN t? Z'9l 00 'ζ ζε6 · ε IL Z9 V SIH N Hidden V
0 L0 L 00' Ί 220 '9 til •9L 99 V V"1V 0 n V0 L0 L 00 'Ί 220' 9 til9L 99 V V "1V 0 n V
3 28"9l 00' ,1 S86' 210' 99 V V1V 3 隱 V3 28 "9l 00 ', 1 S86' 210 '99 V V1V 3 Hidden V
3 86 00' ■I 696 · 00 'SI 8Ζ Ί 99 V V1V ao 隱 V3 86 00 '■ I 696 · 00' SI 8Ζ Ί 99 V V1V ao Oki V
3 L8'9L 00' Ί 66i't7 69 91 1917 99 V V1V VO 隱 V3 L8'9L 00 'Ί 66i't7 69 91 1917 99 V V1V VO Oki V
H 00' Ί εο5·ε 826 "91 LIL'Z 9S V V1V N ΖΠ 謝 V 0) ) 8拏 H 00 'Ίεο5 ・ ε 826 "91 LIL'Z 9S V V1V N ΖΠ Thanks V 0)) 8 Halla
0 g τ0 g τ
00/COOZdT/X3d 請 OAV 0 9 61 00Ί t^98"9 96 V mi 130 £69 隱 V00 / COOZdT / X3d contract OAV 0 9 61 00Ί t ^ 98 "9 96 V mi 130 £ 69 Hidden V
3 n'Li 00Ί 6 6·2 88£·9 6627 96 V 腿 83 269 隱 V3 n'Li 00Ί 6 6 2 88 £ 9 6627 96 V Thigh 83 269 Hidden V
3 iO"9L οο'ι 092 ·ε 2687 002 96 V mi VO 169 匪 V3 iO "9L οο'ι 092 · ε 2687 002 96 V mi VO 169 Marauder V
N L0'9L 00*1 0·8 Wl 96 V ■ N 069 W01VN L0'9L 00 * 1 0.8 Wl 96 VN 069 W01V
0 8i"9L ΟΟΊ 006 "9 ειε'8 L88'2 96 V H人丄 0 689 W01V0 8i "9L ΟΟΊ 006" 9 ειε'8 L88'2 96 V H 0 0 689 W01V
3 9'9l ΟΟΊ 669 "9 £69'L 96 V y人丄 3 889 W01V3 9'9l ΟΟΊ 669 "9 £ 69'L 96 V y people 3 889 W01V
0 8 ' 81 00.1 ηι ·6 912' 96 V a人丄 HO 189 匿 V0 8 '81 00.1 ηι6 912' 96 V a HO 189 concealed V
3 9971 00 -ι 999 "8 099 6εに ε 96 V Z3 989 瞧 V3 9971 00 -ι 999 "8 099 6ε to ε 96 V Z3 989 瞧 V
3 Z9"9l ΟΟΊ 1 2 829 96 V ϋ人丄 Z33 989 W01V3 Z9 "9l ΟΟΊ 1 2 829 96 V ϋPerson 丄 Z33 989 W01V
3 •91 ΟΟΊ 286 WL 96 V il人丄 2 CD 隱 V3 • 91 ΟΟΊ 286 WL 96 V il 2 CD Oki V
3 80 1 ΟΟΊ ε'6 881 '9 £69'2 96 V UL 130 £89 隱 V3 80 1 ΟΟΊ ε'6 881 '9 £ 69'2 96 V UL 130 £ 89 Hidden V
3 08*91 ΟΟΊ 162*8 02S'9 ££9Ί 96 V a人丄 I C 289 隱 V3 08 * 91 ΟΟΊ 162 * 8 02S'9 ££ 9Ί 96 V a person 丄 I C 289 Oki V
3 LO'il ΟΟΊ ^69 8ει ·9 £L0.L 96 V y人丄 30 189 隱 V3 LO'il ΟΟΊ ^ 69 8ει9 £ L0.L 96 V y people 丄 30 189 Oki V
3 L6'9l ΟΟΊ 9^6 '9 ζεον 120 ·0 - 96 V Ul 83 089 W01V3 L6'9l ΟΟΊ 9 ^ 6 '9 ζεον 1200-96 V Ul 83 089 W01V
3 SI ΟΟΊ ^9'9 10 ' 8 WO 96 V UL VO 6Z9 0丄 V3 SI ΟΟΊ ^ 9'9 10 '8 WO 96 V UL VO 6Z9 0 丄 V
N 66 · ΟΟΊ 180*9 ε·6 6^ε ·ο - 96 V a人丄 N 819 W01VN 66 · ΟΟΊ 180 * 9 ε6 6 ^ ε · ο-96 V a N 丄 819 W01V
0 £2"9l ΟΟΊ 8εο·8 ' OL 969*0- 6 V 3Hd 0 LL9 W01V0 £ 2 "9l ΟΟΊ 8εο · 8 'OL 969 * 0- 6 V 3Hd 0 LL9 W01V
3 1?9 ' 1 00*1 618*9 m'Qi S88O- Π V 3Hd 3 919 W01V3 1 ~ 9 '1 00 * 1 618 * 9 m'Qi S88O- Π V 3Hd 3 919 W01V
3 Z9^L οο'ι SLf ^ 69 ' 9S0'£ Π V 3Hd Z3 919 隱 V3 Z9 ^ L οο'ι SLf ^ 69 '9S0' £ Π V 3Hd Z3 919 Oki V
0 00 Ί OSZ'S 910 L 9987 V ョ Hd 233 t^9 隠 V0 00 Ί OSZ'S 910 L 9987 V D Hd 233 t ^ 9 Hidden V
3 68·ει ΟΟΊ 6£9"£ 699. 996'L V 3Hd L33 £19 W01V3 68 · ει ΟΟΊ 6 £ 9 "£ 699.996'L V 3Hd L33 £ 19 W01V
0 E6*n ΟΟΊ ΙΙΖ·9 318 'Ζί 299' I 6 V 3Hd 2 9 隠 V0 E6 * n ΟΟΊ 99 318 'Ζί 299' I 6 V 3Hd 2 9 Hidden V
3 Z9'£l 00 Ί ΙΙΟ'^ £96'IL 989 Ό 6 V 3Hd 9 隱 V3 Z9 '£ l 00 Ί ΙΙΟ' ^ £ 96'IL 989 Ό 6 V 3Hd 9 Oki V
3 L6'£L ΟΟΊ 8^Γ W21 ZLVO V 3Hd 0Z9 H01V3 L6 '£ L ΟΟΊ 8 ^ Γ W21 ZLVO V 3Hd 0Z9 H01V
3 l · οο·ι 898*9 999 'ΖΙ W6'0- Π V 3Hd ao 699 W01V3 l οο · ι 898 * 9 999 'ΖΙ W6'0- Π V 3Hd ao 699 W01V
0 99 "SI 00 Ί 290*9 982. WL - 6 V 3Hd VO 899 瞧 V0 99 "SI 00 Ί 290 * 9 982.WL-6 V 3Hd VO 899 瞧 V
N ·91 οο'ι 889*9 010 176 V 3Hd N Z99 W01VN91 οο'ι 889 * 9 010 176 V 3Hd N Z99 W01V
0 £2'6L ΟΟΊ 9^0 1 18Z'LL 699 ·ε V09 V oad 0 08S 瞧 V0 £ 2'6L ΟΟΊ 9 ^ 0 1 18Z'LL 699 · ε V09 V oad 0 08S 瞧 V
3 0丄 ·61 00 Ί ι'ιι 8f ΊΙ 06S ' V09 V oad 0 6i£ W01V3 0 丄 61 00 Ί ι'ιι 8f ΊΙ 06S 'V09 V oad 0 6i £ W01V
0 L9'8l ΟΟΊ 2 ' 6 m '6 66S V09 V Oiid 3D W01V0 L9'8l ΟΟΊ 2 '6 m' 6 66S V09 V Oiid 3D W01V
D ■81· 00 Ί 99^6 800"0L 09Ζ"ε V09 V OHd ao W01VD ■ 81 · 00 Ί 99 ^ 6 800 "0L 09Ζ” ε V09 V OHd ao W01V
0 "6l οο'ι ε ·6 zn'ii 9^6 ·£ V09 V Odd VO 隱 V0 "6l οο'ι ε · 6 zn'ii 9 ^ 6 · £ V09 V Odd VO Oki V
3 2·81 οο·ι 891 "8 剛 'OL 2'S V09 V OM ao 9i£ W01V 3 281 οο · ι 891 "8 Go 'OL 2'S V09 V OM ao 9i £ W01V
(20)^)8 ^ (20) ^) 8 ^
τ s τ s
f/,600/COOZdf/X3d 請 OOZ OAV 009738 f /, 600 / COOZdf / X3d contract OOZ OAV 009738
1 52 表 8(その 3)  1 52 Table 8 (Part 3)
ATOM 694 CG2 THR A 96 2.246 6.132 1. ,489 1 .00 17.26 CATOM 694 CG2 THR A 96 2.246 6.132 1., 489 1 .00 17.26 C
ATOM 695 C THR A 96 1.747 8.685 2. ,033 1 .00 15.93 CATOM 695 C THR A 96 1.747 8.685 2., 033 1.00 15.93 C
ATOM 696 0 THR A 96 0.546 8.873 1. 815 1 .00 15.53 0ATOM 696 0 THR A 96 0.546 8.873 1.815 1 .00 15.53 0
ATOM 697 N ALA A 97 2.705 9.141 1. 230 1 .00 15.22 NATOM 697 N ALA A 97 2.705 9.141 1.230 1 .00 15.22 N
ATOM 698 CA ALA A 97 2.375 9.920 0. ,042 1 .00 16.08 CATOM 698 CA ALA A 97 2.375 9.920 0., 042 1 .00 16.08 C
ATOM 699 CB ALA A 97 3.659 10.425 -0. 629 1 .00 15.68 CATOM 699 CB ALA A 97 3.659 10.425 -0.629 1 .00 15.68 C
ATOM 700 C ALA A 97 1.543 9.113 - 0. 953 1, .00 16.40 CATOM 700 C ALA A 97 1.543 9.113-0.953 1, .00 16.40 C
ATOM 701 0 ALA A 97 0.694 9.664 -1. 652 1, .00 16.60 0ATOM 701 0 ALA A 97 0.694 9.664 -1.652 1, .00 16.60 0
ATOM 702 N GLN A 98 1.780 7.805 - 1. 008 1, .00 16.30 NATOM 702 N GLN A 98 1.780 7.805-1.008 1, .00 16.30 N
ATOM 703 CA GLN A 98 1.059 6.955 -1. 946 1, .00 16.76 CATOM 703 CA GLN A 98 1.059 6.955 -1.946 1, .00 16.76 C
ATOM 704 CB GLN A 98 1.805 5.634 -2. 162 1, .00 16.41 CATOM 704 CB GLN A 98 1.805 5.634 -2. 162 1, .00 16.41 C
ATOM 705 CG GLN A 98 3.204 5.787 -2. 772 1, .00 15.89 CATOM 705 CG GLN A 98 3.204 5.787 -2. 772 1, .00 15.89 C
ATOM 706 CD GLN A 98 4.235 6.319 -1. 777 1, .00 16.02 CATOM 706 CD GLN A 98 4.235 6.319 -1.777 1, .00 16.02 C
ATOM 707 0E1 GLN A 98 4.227 5.954 -0.608 1. .00 16.24 0ATOM 707 0E1 GLN A 98 4.227 5.954 -0.608 1. .00 16.24 0
ATOM 708 NE2 GLN A 98 5.139 7.168 -I. 251 1, .00 17.30 NATOM 708 NE2 GLN A 98 5.139 7.168 -I. 251 1, .00 17.30 N
ATOM 709 C GLN A 98 -0.375 6.685 -1. 509 1, .00 17.02 CATOM 709 C GLN A 98 -0.375 6.685 -1.509 1, .00 17.02 C
ATOM 710 0 GLN A 98 -1.242 6.451 -2.346 1. .00 ?6.85 0ATOM 710 0 GLN A 98 -1.242 6.451 -2.346 1. .00? 6.85 0
ATOM 711 N ILE A 99 -0.625 6.719 -0. 203 1. .00 16.87 NATOM 711 N ILE A 99 -0.625 6.719 -0. 203 1. .00 16.87 N
ATOM 712 CA ILE A 99 -1.976 6.506 0.304 1. .00 17.74 CATOM 712 CA ILE A 99 -1.976 6.506 0.304 1. .00 17.74 C
ATOM 713 CB ILE A 99 -1.953 6.083 1. 789 1. .00 17.48 CATOM 713 CB ILE A 99 -1.953 6.083 1.789 1. .00 17.48 C
ATOM 714 CG2 ILE A 99 -3.383 5.889 2. 304 1. .00 19.30 cATOM 714 CG2 ILE A 99 -3.383 5.889 2.304 1. .00 19.30 c
ATOM 715 CGI ILE A 99 - 1.170 4.772 1. 928 1. .00 17.35 cATOM 715 CGI ILE A 99-1.170 4.772 1.928 1. .00 17.35 c
ATOM 716 CD1 ILE A 99 -0.867 4.365 3.368 1. .00 18.26 cATOM 716 CD1 ILE A 99 -0.867 4.365 3.368 1. .00 18.26 c
ATOM 717 C ILE A 99 -2.761 7.811 0. 119 1. ,00 17.60 cATOM 717 C ILE A 99 -2.761 7.811 0.119 1., 00 17.60 c
ATOM 718 0 ILE A 99 -3.970 7.787 - 0. 105 1. ,00 18.55 0ATOM 718 0 ILE A 99 -3.970 7.787-0.105 1., 00 18.55 0
ATOM 719 N Gし Y A 100 -2.075 8, 947 0.201 i. , 00 16.94 NATOM 719 N G then Y A 100 -2.075 8, 947 0.201 i., 00 16.94 N
ATOM 720 CA GLY A 100 -2.755 10.218 - 0. 018 1. 00 16.88 cATOM 720 CA GLY A 100 -2.755 10.218-0.0018 1.00 16.88 c
ATOM 721 C GLY A 100 -2.757 11.220 1. 121 1. 00 16.29 cATOM 721 C GLY A 100 -2.757 11.220 1.121 1.00 16.29 c
ATOM 722 0 GLY A 100 -2.104 11.014 2. 141 1. 00 16.50 0ATOM 722 0 GLY A 100 -2.104 11.014 2.141 1.00 16.50 0
ATOM 723 N ALA A 101 -3.506 12.308 0. 937 1. 00 15.76 NATOM 723 N ALA A 101 -3.506 12.308 0.937 1.00 15.76 N
ATOM 724 CA ALA A 101 -3.606 13.367 1. 935 1. 00 15.11 CATOM 724 CA ALA A 101 -3.606 13.367 1.935 1.00 15.11 C
ATOM 725 CB ALA A 101 -4.277 12.822 3.220 1. 00 15.69 cATOM 725 CB ALA A 101 -4.277 12.822 3.220 1.00 15.69 c
ATOM 726 C ALA A 101 -2.222 13.937 2. 258 1. 00 14.69 c 0 86 '02 00 'I 9l9'8l- 9671 t^s ι Z8L V aav 0 i W01V 0 0^ 2 00" I S 8卜 Z9071 62ΓΙΙ 181 V 3HV 0 隠 V N 6 K OO'l £29'S2- 089 · 2£8'Zl 81 V DHV Z N z i WOiV N 69 ^£ OO'L 26Z'92- 69'9l 880'Μ v 3HV IHN ι ι H01V 0 ε ε oo" ι 90.S2- £9i"9l 89E'£l 181 V 0HV Z3 o 隠 V N 6·εε oo'i 820"9l 9εに ει 8L V DHV 3N mi WOiV 3 οζ"ΐε ΟΟΊ 680'£Z- m ·ει Z81 V DHV ao mi noiv 0 0 '62 00 "I 889 Ί2- 26071 ΐ9^'ει 18 ί V DHV 03 隱 V 3 19'9Ζ OO'L LW - W91 92に 21 181 V 0HV 93 mi 隠 V 0 'ΐζ οο 962'61- l£6*9l 18ί V DHV vo 隱 V H 09"£2 00 "L 989'6L- 8·Μ 22に II 18L V oav N mi WO丄 V 0 Ζ8'91 00 Ί £99 Ζ8 Ό ΡΟί V IV 0 8 丄 W01V 0 ε ·9ΐ οο'ι U9'9 ΕΖ9"12 8 .0 ΡΟί V VIV 0 隠 V 3 22'91 00 Ί 222 '9 999 "6L £L9"L ΡΟί V IV 93 W01V 3 00 Ί 819"9 £91 'QZ ζεε ·ο ΟΙ V VIV. V3 W01V N Li'9l 00 "L 99Ζ· 899 '61 ^ 1 ·0 ΡΟί V VIV N W01V 0 fr6'9l OO'L 886 ' 608 L 198 '0 - εοι ν 311 0 ε WOIV 0 02"9l OO'l 990 · ^09 "8 L 8 '0- εοι ν 311 0 zn 隠 V 3 £L 71 OO'l 266Ό 999 *02 ε8ο·ε- εοι ν 311 Lao IPl WOIV 3 0Z'9L OO'l 0£8"l LPQ'QZ Wl - εοι ν 311 ID3 0P1 匪 V 3 21 OO'l Z26'2 Ζ60·81 οι ·ε- εοι ν 311 233 6£1 W01V 3 i8'M OO'l LZO'Z IE9"8L εοι ν 311 93 8£l 隱 V 3 08' OO'l 6 8L Z89"0- SOL ν. 311 V3 HL 隠 V N IS' OO'l 6fr9 ·1 £09'9l 66f Ό- εοι ν 311 N 992 隠 V 0 Π' Ι 00*1 frl9.0 9'9l l ' 0 Z0L ν dSV 0 £I W01V 3 LO'frl OO'l 99^*1 920'9l 900 "0- 201 ν dSV 3 HL H01V 0 02"9L OO'l 261 ·0 - 'El ΟΠ'ΐ: ζοι ν dSV zao ZIL 隱 V 0 82'9l OO'l 208 Ί 129^1 20L V dSV ιαο ZIL W01V 3 I9'9l OO'l 189-0 8iに m'z 201 V dSV DO i%L 隱 V 3 0 · OO'l 99£"0 086'εΐ 926 "0 201 V dSV ao οε IN01V 3 ZS' OO'l 09 ' I 66t · 100 "0 20L V dSV V3 隱 V N ε 'M οο'ι 9S3'L 686 'Π ε·ι- 201 V dSV H UL W01V 0 2"Sl 00 Ί Z96"L- 101 V IV 0 LZL 隱 V ATOM 726 C ALA A 101 -2.222 13.937 2.258 1.00 14.69 c 0 86 '02 00 'I 9l9'8l- 9671 t ^ s ι Z8L V aav 0 i W01V 0 0 ^ 2 00 "IS 8 box Z9071 62ΓΙΙ 181 V 3HV 0 Hidden VN 6 K OO'l £ 29'S2- 089 · 2 £ 8'Zl 81 V DHV ZN zi WOiV N 69 ^ £ OO'L 26Z'92- 69'9l 880'Μ v 3HV IHN ι ι H01V 0 ε ε oo "ι 90.S2- £ 9i" 9l 89E '£ l 181 V 0HV Z3 o concealed VN 6εε oo'i 820 ”9l 9ε ει 8L V DHV 3N mi WOiV 3 οζ” ΐε ΟΟΊ 680' £ Z- m · ει Z81 V DHV ao mi noiv 0 0 ' 62 00 "I 889 Ί2- 26071 ΐ9 ^ 'ει 18 ί V DHV 03 Odd V 3 19'9Ζ OO'L LW-W91 92 21 181 V 0HV 93 mi Hidden V 0' ΐζ οο 962'61- l £ 6 * 9l 18ί V DHV vo Oki VH 09 "£ 200" L 989'6L- 8Μ22 to 18L V oav N mi WO 丄 V 0 Ζ8'91 00 Ί £ 99 Ζ8 Ό ΡΟί V IV 08 丄 W01V 0 ε · 9ΐ οο'ι U9'9 ΕΖ9 "12 8.0 ΡΟί V VIV 0 concealed V 3 22'91 00 Ί 222 '9 999" 6L £ L9 "L ΡΟί V IV 93 W01V 3 00 Ί 819" 9 £ 91 'QZ ζεε ο ΟΙ V VIV.V3 W01V N Li'9l 00 "L 99Ζ 899 '61 ^ 1 · 0 V VIV N W01V 0 fr6'9l OO'L 886' 608 L 198 '0-εοι ν 311 0 ε WOIV 0 02 "9l OO'l 990 ・ ^ 09" 8 L 8 '0- εοι ν 311 0 zn Hidden V 3 £ L 71 OO'l 266Ό 999 * 02 ε8ο · ε- εοι ν 311 Lao IPl WOIV 3 0Z'9L OO'l 0 £ 8 "l LPQ'QZ Wl-εοι ν 311 ID3 0P1 Maraud V 3 21 OO 'l Z26'2 Ζ60 ・ 81 οι ・ ε- εοι ν 311 233 6 £ 1 W01V 3 i8'M OO'l LZO'Z IE9 "8L εοι ν 311 93 8 £ l Hidden V 3 08'OO'l 6 8L Z89 "0- SOL ν. 311 V3 HL concealed VN IS 'OO'l 6fr91 £ 09'9l 66f Ό-εοι ν 311 N 992 concealed V0 Z0L ν dSV 0 £ I W01V 3 LO'frl OO'l 99 ^ * 1 920'9l 900 "0- 201 ν dSV 3 HL H01V 0 02" 9L OO'l 261 · 0-'El ΟΠ'ΐ: ζοι ν dSV zao ZIL hidden V 0 82'9l OO'l 208 Ί 129 ^ 1 20L V dSV ιαο ZIL W01V 3 I9'9l OO'l 189-0 8i m'z 201 V dSV DO i% L hidden V 3 0 OO'l 99 £ "0 086'εΐ 926" 0 201 V dSV ao οε IN01V 3 ZS 'OO'l 09' I 66t100 '0 20L V dSV V3 Odd VN ε' M οο'ι 9S3'L 686 ' Εει-201 V dSV H UL W01V 0 2 "Sl 00 Ί Z96" L- 101 V IV 0 LZL Hidden V
( (½)8攀 ((½) 8 climbs
ε s τ ε s τ
C.600/COOrdf/X3d t'ifCTO/l-OOZ ΟΛ\ 3 •61 00· I w - 296 ^1 261 V N13 V3 LLP I WOiV N SO'OZ 00 'L 866'9- 8Ζ6·Μ οοε'ει 261 V N1D N 9 I H01V 0 9£"02 00' I 868 '9- 000'2l L61 V SAO 0 ^1 WOIV 3 ' 02 OO'l S S ·9 - £S8"9L 9LS 1 161 V SAO 3 t^t^l WOiV S 98 "92 OO'l 8'8- ίζΐ ' 1 WW 161 V SAO OS iL l WOIV 3 OO'l 0Z8'8- 6U"9l Z9S"CL 161 V SAO 90 ZL l WOIV 3 SVOZ OO'l 8£0"8- 60Z"9l 19Z'21 L6L V SAD V3 Ufl WO丄 V N £S"6l 00Ί 0£9-8- 08 "9l 11 L61 V SAO N OL^l WOiV 0 £9*81 OO'l "01- WSl S6S"0l 061 V H3S 0 mi H01V 0 W61 OO'l Z8S'6- 029 '91 829.01 061 V ϋョ S 0 89 H01V 0 20'8l OO'l 966 ·8 - Zll'9l 'L 061 V ϋョ S 30 i9t^L 隠 V 3 09*81 OO'l Z60'6- S16 1 £8S'8 061 V ϋョ S 93 mi WOIV 3 99 "81 OO'l ZSO'Ol- fsr6 061 V i)ョ S V3 mi WOIV N 89 "81 OO'l 09ΠΙ- 20C 1 9ZZ'6 061 V ϋョ S N 9 1 WOiV 0 l 81 OO'l £0371- t^9£ '81 Ζ06ΌΙ 681 V dSV 0 99^1 WOIV 3 Z9"8l OO'l 8Zf '21- 02971 S16'6 681 V dSV 0 29 WOiV 0 ZZ' OO'l Gtrzi- 26 'ει 910*6 681 V dSV ZQO mi WOIV 0 98'8l OO'l 66 21- 0^8 681 V dSV ΐαθ 09 WOIV 3 £8*61 OO'l 8'2l- Z92'8 681 V dSV DO mi WOIV 0 £に 6〖 00 Ί 228'£l- £69*6 681 V dSV 93 89^1 WOIV 3 90*61 OO'l 6SZ'£l- 8E071 ιζι· 681 V dSV VO Z9H WOIV H 6·81 OO'l 096 · I- 2S9 1 W6 681 V dSV N 9S WOIV 0 9t7'8t OO'l οιε·9ΐ - 8£S"9l 6 ·8 881 V 3dV 0 mi WOIV 3 9·61 OO'l 8Sに 91- m'Ll 68Γ6 881 V 3 i WOIV N £i'8Z OO'l 9E6-22- 9Z ·6 881 V m Z N SSfl WOIV N 88 '82 OO'l m'QZ- QOZ 'ZZ S£L ·6 881 V D¾V IHN ZiPl WOIV 3 06 "ZZ OO'l 9ΡΠΖ- 16 ' 12 6 0'6 881 V OdV 10 IS WOIV N OO'l 00 ΊΖ- LU'U 9£9'8 88i v sav ost^i 賺 v 3 08 OO'l SZZ'OZ- 989 "6t εοζ·8 881 V m Q 6 I WOIV 3 η'ΐι oo*i in'si- 69S'6l 06£ ·6 881 V 93 8 WOiV 3 Z6"L2 OO'l ·81- 9 81 881 v oy go i woiv 3 89 "02 OO'l 89£ L- 9l0'8l 610'OL 88L v oyv O i woiv N οε· oo'i 882'8l- 966.91 881 V OdV N 9^L HOiV C.600 / COOrdf / X3d t'ifCTO / l-OOZ ΟΛ \ 3 • 61 00I w-296 ^ 1 261 V N13 V3 LLP I WOiV N SO'OZ 00 'L 866'9- 8Ζ6Μ οοε'ει 261 V N1D N 9 I H01V 0 9 £ "02 00' I 868 '9- 000'2l L61 V SAO 0 ^ 1 WOIV 3 '02 OO'l SS9-£ S8 "9L 9LS 1 161 V SAO 3 t ^ t ^ l WOiV S 98" 92 OO'l 8'8 -ίζΐ '1 WW 161 V SAO OS iL l WOIV 3 OO'l 0Z8'8- 6U "9l Z9S" CL 161 V SAO 90 ZL l WOIV 3 SVOZ OO'l 8 £ 0 "8-60Z" 9l 19Z'21 L6L V SAD V3 Ufl WO 丄 VN £ S "6l 00Ί 0 £ 9-8- 08" 9l 11 L61 V SAO N OL ^ l WOiV 0 £ 9 * 81 OO'l "01- WSl S6S" 0l 061 V H3S 0 mi H01V 0 W61 OO'l Z8S'6- 029 '91 829.01 061 V length S 0 89 H01V 0 20'8l OO'l 9668-Zll'9l 'L 061 V length S 30 i9t ^ L Hidden V 3 09 * 81 OO'l Z60'6- S16 1 £ 8 S'8 061 V S S 93 mi WOIV 3 99 "81 OO'l ZSO'Ol- fsr6 061 V i) S S V3 mi WOIV N 89" 81 OO'l 09ΠΙ-20C 1 9ZZ'6 061 V ϋ SN 91 WOIV 0 l 81 OO'l £ 0371- t ^ 9 £ '81 Ζ06ΌΙ 681 V dSV 0 99 ^ 1 WOIV 3 Z9 "8l OO'l 8Zf '21-02971 S16'6 681 V dSV 0 29 WOiV 0 ZZ 'OO'l Gtrzi- 26' ει 910 * 6 681 V dSV ZQO mi WOIV 0 98'8l OO'l 66 21- 0 ^ 8 681 V dSV ΐαθ 09 WOIV 3 £ 8 * 61 OO'l 8'2l- Z92'8 681 V dSV DO mi WOIV 0 £ 6 〖00 228 228 '£ l- £ 69 * 6 681 V dSV 93 89 ^ 1 WOIV 3 90 * 61 OO'l 6SZ '£ l- 8E071 ιζι · 681 V dSV VO Z9H WOIV H 6.81 OO'l 096I- 2S9 1 W6 681 V dSV N 9S WOIV 0 9t7'8t OO'l οιε · 9ΐ-8 £ S "9l 6・ 8 881 V 3dV 0 mi WOIV 3 9 ・ 61 91- m'Ll 68Γ6 881 V 3i WOIV N £ i'8Z OO'l 9E6-22- 9Z ・ 6 881 V m ZN SSfl WOIV N 88 '82 OO'l m'QZ- QOZ 'ZZ S £ L6 881 V D¾V IHN ZiPl WOIV 3 06 "ZZ OO'l 9ΡΠΖ- 16' 12 6 0'6 881 V OdV 10 IS WOIV N OO'l 00 ΊΖ- LU'U 9 £ 9'8 88i v sav ost ^ i Note v 3 08 OO'l SZZ'OZ- 989 "6t εοζ8 881 V m Q 6 I WOIV 3 η'ΐι oo * i in ' si- 69S'6l 06 £ 6 881 V 93 8 WOiV 3 Z6 "L2 OO'l81- 9 81 881 v oy go i woiv 3 89" 02 OO'l 89 £ L- 9l0'8l 610'OL 88L v oyv O i woiv N οεoo'i 882'8l- 966.91 881 V OdV N 9 ^ L HOiV
^ 9 I^ 9 I
eZ.600/C00^df/X3d eZ.600 / C00 ^ df / X3d
rano ί OAV N I6"£l 00· I 10S S0'9l 91ί'Ρ V N 8291 隱 Vrano ί OAV N I6 "£ l 00 · I 10S S0'9l 91ί'Ρ VN 8291 Hidden V
0 69'Sl 00· I U9 L L 'f V Ί Λ 0 91 隱 V0 69'Sl 00I U9 L L 'f V Ί Λ 0 91 Oki V
3 82·ει Z9Z 1 929 "fr HZ V 1VA 3 9291 隨 V3 82εε Z9Z 1 929 "fr HZ V 1VA 3 9291 Function V
3 ζζ'ει 00· I Z96'6L 8£Z'9 ειζ V IVA 230 9291 WOiV3 ζζ'ει 00I Z96'6L 8 £ Z'9 ειζ V IVA 230 9291 WOiV
D 00· I 9^9 '9- ni'i t^60'Z ειζ V 1VA 103 291 H01VD 00I 9 ^ 9 '9- ni'i t ^ 60'Z ειζ V 1VA 103 291 H01V
3 6 00· I 682 '9- U8'8l LLl '9 V IVA 93 £291 W01V o o 3 6 00I 682 '9- U8'8l LLl' 9 V IVA 93 £ 291 W01V o o
0 26·εΐ 00· I 9£L '9- 69£'8l V IVA V3 91 WO丄 V 0 26εε 00I 9 £ L '9- 69 £' 8l V IVA V3 91 WO 丄 V
N
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00· I L' - 1 09f'6L Ζΐ 'ΐ ζιζ V IVA N 1291 W01VN
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00IL '-1 09f'6L Ζΐ' ΐ ζιζ V IVA N 1291 W01V
0 ΕΓ91 00· I 丄 96'0— ΖΙΟ'02 0 9·8 96L V aョ s 0 209 L 隨 V0 ΕΓ91 00 · I 丄 96'0— ΖΙΟ'02 0 9.8 96L V a s 0 209 L Custom V
3 9 91 00' I 912'6L 9887 961 V 3 L09L W01V3 9 91 00 'I 912'6L 9887 961 V 3 L09L W01V
0 tO"9l 00 'I 9127- 29 SI fr96'8 96L V yョ s DO 0091 隱 V0 tO "9l 00 'I 9127- 29 SI fr96'8 96L V y s DO 0091 Oki V
3 89*91 00' I 996 *91 96L V aョ s 93 66PI IN01V3 89 * 91 00 'I 996 * 91 96L V a s 93 66PI IN01V
3 t^9 -9L 00· I 6 - 81 οε ·8 96L V U3S V3 S6PI 匪 V3 t ^ 9 -9L 00I 6-81 οε8 96L V U3S V3 S6PI Marauder V
N 99'9l 00' I 8 'ε— 26fr'8l 809 "6 961 V aョ s N 16PI W01VN 99'9l 00 'I 8' ε- 26fr'8l 809 "6 961 V a s N 16PI W01V
0 O'Zl 00· I 22 '02 2Ζ8·8 V dSV 0 96 I 隠 V0 O'Zl 00I 22 '02 2Ζ8 V dSV 0 96 I Hidden V
0 9 ·91 00· I 8S8'£- 899 '61 '6 Ml V dSV 3 S6fl W01V0 991 00I 8S8 '£-899 '61' 6 Ml V dSV 3 S6fl W01V
0 09'9l 00 'I m Ί~ 2Lf "6L V dSV IN01V0 09'9l 00 'I m Ί ~ 2Lf "6L V dSV IN01V
0 OO'l 892·9- 61 V dSV ιαο £6Pl W01V0 OO'l 892.9-61 V dSV ιαο £ 6Pl W01V
3 SI OO'L SLO'I- 991 *0Z V dSV DD 26W 隠 V3 SI OO'L SLO'I- 991 * 0Z V dSV DD 26W Hidden V
3 20*91 OO'L l '9- 269"6l WOl V dSV 93 I6 l 隠 V3 20 * 91 OO'L l '9- 269 "6l WOl V dSV 93 I6 l Hidden V
0 08'9L OO'l £99 '^- £68"6L 686*01 V dSV O 06 W01V0 08'9L OO'l £ 99 '^-£ 68 "6L 686 * 01 V dSV O 06 W01V
N 9fr'9L OO'l S81 "f- 2i6'8l 610 I V dSV N 6SPi 隠 VN 9fr'9L OO'l S81 "f-2i6'8l 610 I V dSV N 6SPi Hidden V
0 Ol'Ll OO'l 869*2- 8 ·0Ζ 99871 86L V 人， 3 0 8SPI 隠 V0 Ol'Ll OO'l 869 * 2- 8 · 0Ζ 99871 86L V person, 3 0 8SPI hidden V
3 εζ·9ΐ OO'l ειε·6ΐ E6l V AID 3 mi W01V3 εζ9ΐ OO'l ειε6ΐ E6l V AID 3 mi W01V
3 00·【 19 - 2S8'£l £61 V 人 13 VO 92PI N01V3 00 · [19-2S8 '£ l £ 61 V people 13 VO 92PI N01V
N OO'l I9L ·£- 9L6'9l £6L V AID N SSPl 隠 VN OO'l I9L £-9L6'9l £ 6L V AID N SSPl Hidden V
0 S0'6L OO'l 828 896 '91 916 1 Z61 V N10 0 PSPl 隠 V0 S0'6L OO'l 828 896 '91 916 1 Z61 V N10 0 PSPl Hidden V
0 26'8L OO'L £12' - £'9l Z6L V NID 3 mi 隱 V0 26'8L OO'L £ 12 '-£' 9l Z6L V NID 3 mi Oki V
N 86 "f 2 OO'L 092 · 'oi £86*21 261 V NID Z3N Z8PI W01VN 86 "f 2 OO'L 092 · 'oi £ 86 * 21 261 V NID Z3N Z8PI W01V
0 OO'l 982*9- 90.21 SOL' 261 V NID 130 18PI 隠 V0 OO'l 982 * 9- 90.21 SOL '261 V NID 130 18PI Hidden V
3 OO'L 0LL *9- 608 ·11 8S8"El 261 V NID ao OSPl miv3 OO'L 0LL * 9- 608 11 8S8 "El 261 V NID ao OSPl miv
0 OO'l £Z6"E- £9S l 66 l 261 V N19 33 61PI miv0 OO'l £ Z6 "E- £ 9S l 66 l 261 V N19 33 61PI miv
0 91 2 OO'l οιε·ト QP 'Pl 261 V ΝΊΟ 83 81PI 謝 V 0 91 2 OO'l οιε ト QP 'Pl 261 V ΝΊΟ 83 81PI
(9 (½)8拏 (9 (½) 8 Halla
S S IS S I
C.600/COOZdf/X3d 1 ^ 難 OOZ OAV H 0 ' 00•I S2r6- 9E8 S8S '01 IZ V kid H 1991 W01VC.600 / COOZdf / X3d 1 ^ Difficult OOZ OAV H 0 '00 • I S2r6- 9E8 S8S '01 IZ V kid H 1991 W01V
0 00 Ί LQi'il- LLfL 89 '6 LIZ V ΠΊ3 0 0991 W01V0 00 Ί LQi'il- LLfL 89 '6 LIZ V ΠΊ3 0 0991 W01V
3 90· 00 'I WOl- 7 289 "6 LIZ v nio 3 699L W01V3 90 00 'I WOl- 7 289 "6 LIZ v nio 3 699L W01V
0 00 •I IS'6 - Z60"£ 062 'S LIZ V Π13 230 899L WOiV0 00 • I IS'6-Z60 "£ 062 'S LIZ V Π13 230 899L WOiV
0 00 ■I 08'0l— £66 "2 690'丄 LiZ V ma lョ 0 991 HOiV0 00 ■ I 08'0l— £ 66 "2 690 '丄 LiZ V malo 0 991 HOiV
3 -zz 00 •I 898 -6- f09'£ LIZ v ms αο 9S91 HOiV3 -zz 00I898 -6- f09 '£ LIZ v ms αο 9S91 HOiV
3 90.22 00 •I ZZl '6- 020 "I LIZ v nio 999L WOIV3 90.22 00IZZl '6- 020 "I LIZ v nio 999L WOIV
3 96*02 00 "L OEO'OL- 2Z9'9 'L LIZ v nio fr99L WOIV3 96 * 02 00 "L OEO'OL- 2Z9'9 'L LIZ v nio fr99L WOIV
3 69·02 00 •I ·6 - Z8Z'9 S ·8 LiZ V mo vo £S9l 隱 V3 6902 00I6-Z8Z'9 S8 LiZ V mo vo £ S9l Oki V
N 00 Ί 911 ·6- m'L ZZVL LiZ V niD N Z99L WOIN 00 Ί 911 · 6-m'L ZZVL LiZ V niD N Z99L WOI
0 l 61 00 ■I 980 - 990 '8 9L2 V 人 Ί3 0 L99L H01V0 l 61 00 I 980-990 '8 9L2 V person Ί3 0 L99L H01V
3 U'8l 00 •I 90·8 - 8£S'8 'L 912 V 人" 13 0 0991 WOIV3 U'8l 00 • I 90 · 8-8 £ S'8 'L 912 V people "13 0 0991 WOIV
3 £9'1L 00 -L 8S0'8- 29·6 912 V AID VD 6 91 隠 V3 £ 9'1L 00 -L 8S0'8- 29.6 912 V AID VD 6 91 Hidden V
N Vi'Ll 00 "L ει 9 - 96に 01 822 '9 9L2 V 人つ 3 N WOIVN Vi'Ll 00 "L ει 9-96 to 01 822 '9 9L2 V people 3 N WOIV
0 0 ·91 00 ■I ' - εに 21 £ΙΓ9 SL2 V 0 i HOiV0 0 · 91 00 ■ I '-ε 21 £ ΙΓ9 SL2 V 0 i HOiV
3 9£"9l 00 'I 609-9- ε ' 6£i"9 912 V dill 3 9 91 WOiV3 9 £ "9l 00 'I 609-9- ε' 6 £ i" 9 912 V dill 3 9 91 WOiV
3 98'9l 00 •I W9 - 969"9 SL2 V dH丄 2H3 91 WOIV3 98'9l 00 • I W9-969 "9 SL2 V dH 丄 2H3 91 WOIV
3 08'9L 00' ■L Ι0Γ9- 8 2 '9 2ε8·ε SiZ V d 丄 £Z3 i H01V3 08'9L 00 '■ L Γ0Γ9- 8 2' 9 2ε8 ・ ε SiZ V d 丄 £ Z3 i H01V
3 96'9l 00 Ί 686 969 "i 809 "L 912 V 丄 2Z3 WOIV3 96'9l 00 Ί 686 969 "i 809" L 912 V 丄 2Z3 WOIV
N 20· I 00' Ί 2£6'6 6 9Ί S12 V da丄 13N 91 HOiVN 20I 00 'Ί 2 £ 6'6 6 9Ί S12 V da 丄 13N 91 HOiV
3 90'9l 00 Ί LW01 'z 912 V dil丄 ιαο mi WOIV3 90'9l 00 Ί LW01 'z 912 V dil 丄 ιαο mi WOIV
3 Z 91 00 Ί 928· 912 V da丄 £30 oni HOIV3 Z 91 00 Ί 928912 V da 丄 £ 30 oni HOIV
0 98'9L 00 Ί 6ΖΓ - 08'8
Figure imgf000157_0001
1Z V dil丄 Z30 6£9l WOIV0 98'9L 00 Ί 6ΖΓ-08'8
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1Z V dil 丄 Z30 6 £ 9l WOIV
3 9£'9L 00' 'L 16 '8 S V ZQ 8£9L WOIV3 9 £ '9L 00' 'L 16' 8 S V ZQ 8 £ 9L WOIV
3 20"9l 00' 'I 691 ·01 9Z8"£ V da丄 33 ZE9L WOIV 3 20 "9l 00 '' I 691 01 9Z8" £ V da 丄 33 ZE9L WOIV
9 SI 00' Ί arv- 21 01 's 912 V da丄 80 9£9L WOIV 9 SI 00 'Ί arv- 21 01's 912 V da 丄 80 9 £ 9L WOIV
3 98'91 00' Ί £90"9- 9SZ'S 912 V da丄 V3 S89L WOIV3 98'91 00 'Ί £ 90 "9-9SZ'S 912 V da 丄 V3 S89L WOIV
N 6 SI 00' Ί ' - z ει V 丄 N WOIVN 6 SI 00 'Ί'-z ει V 丄 N WOIV
0 0 ^1 00' l 628.2- ε 'ει 6f8"9 IZ V ϋョ s 0 mi WOiV0 0 ^ 1 00 'l 628.2- ε' ει 6f8 "9 IZ V s s 0 mi WOiV
0 L2'9l 00' Ί OZL'i- ο^-ει 890 '9 VIZ V iJ3S 0 ZE9L HOIV0 L2'9l 00 'Ί OZL'i- ο ^ -ει 890' 9 VIZ V iJ3S 0 ZE9L HOIV
0 ■91 00' Ί 6697- ~z IZ V aョ s 30 L£9L WOIV0 ■ 91 00 'Ί 6697- ~ z IZ V ao s 30 L £ 9L WOIV
3 H^l 00' Ί VIZ V ao 0£9L WOIV3 H ^ l 00 'Ί VIZ V ao 0 £ 9L WOIV
3 00 Ί IS9"£- 2S6'm 6S IZ V V3 6291 WOIV 3 00 Ί IS9 "£-2S6'm 6S IZ V V3 6291 WOIV
991991
C.600/COO∑:df/X3d 0 08 "£2 00 *L H)9'l- 106 '6 ιοε V丄 VN 13 L68L W1V13H 3 9i'£2 00 Ί 12 2 - 09£ -ε 9^6'0l ιοε v 1VN 9D 0681 W1V13H 3 96 ΊΖ 00" I i fl- £ Ί 809'OL ιοε v 1VN 90 688L HiVi3H 3 οε'εζ oo Ί SL6'2- ( ·1 L92'6 ιοε ν 丄 VN 8881 W1V13H 3 88Έ2 00 Ί 2 ' 2 - 602 '8 ιοε ν丄 VN £3 88L W1V13H 0 ·^ΊΙ 00 "L S9£'0 ~i L61 ιοε ν丄 VN 10 988L H1V13H 3 Wll 00 Ί ISに 0 16£'8 ιοε ν 1VN 23 9881 W1V13H 3 ES'6l OO'L L69 "0 16 '01 L9S ·6 ιοε ν 1VN L3 t^88L HiVi3H 3 00" I 862"l 98 6 926 '8 ιοε ν iVN 3 9891 W1V13H N 68 "02 00"l 689*0 890 '8 862 "6 ιοε ν 丄 VN N Z88L HiVi3H 0 ^VZZ OO'l i'9l- 909 *8 9i9"8 \ΖΖ ν ΝΊ3 0 f89L INOiV 0 Wll OO'l Zl6'9l- 201 ·8 622 "6 ν N13 3 E89L 隱 V N n~u OO'L 16 ' 8 62' \/ι ν ΝΠ3 Z3N Z89L W01V 0 98*82 OO'l izrsi- 262 '9 698"£l ΙΖΖ V N1D iao 1891 隠 V 3 61 " 2 OO'l SO U9*£L VIZ2 V ΝΊ3 0891 隱 V 0 68 " 2 OO'l ISO' - SZ£ 71 V 2 V ΝΊ3 DO 6i9l 隠 V 0 ΐ ^Ζ 00 "L 'i OiO'U VL2Z V ΝΊ3 ao 8i9l 隠 V 3 i 'u oo'i I20'9l- OS ·8 I96"0l VI V N"ID o Z29L 隱 V N οε'ιζ oo'i S6i'6 f8i"0l
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V N13 N 9191 IN01V 0 8 02 OO'l ト 092 '01 990 L 122 V V1V 0 S291 隱 V 0 i8"0Z OO'l WT91- L98"0L f9£ "LI ΪΖΖ V V1V 3 謝 V' 3 IS "02 OO'l Zl6'9l- IWli 001 ΊΪ ΙΖΖ V V1V 83 £291 W01V 3 18Ό2 OO'l 66£"9L- Vl 980'Ll 122 V V1V O 2丄 91 瞧 V N l'QZ OO'l 6E6"£l- 8ZL 71 £ Ι ill V V，V N U91 腿 V 0 OO'l 0L8"£L- LLZ'll 022 V SAO 0 o W01V 3 se'iz oo'i PZL'll 9171 022 V SAO 0 6991 隱 V S OO'l 6εε'6- L90'£l 022 V SA3 OS 899L 隠 V 3 SS'ZZ OO'l £91 'LL- Z80 I QZZ V SAO 80 Z99L W01V 3 88· OO'l 'li- 9ΓΙΙ 99071 Z V SAO VO 9991 隠 V N 89*12 OO'l 6 - Off "01 ^LZ'Zi ΟΖΖ V SAO N S991 隱 V 0 LL "LZ OO'l 91 ΌΙ- (M'Ol ZLZ'Q 612 V AID 0 mi WOiV 3 89'LZ OO'l ε^·οι- 9£8"6 99ΠΙ 6 V人 13 0 £991 WO丄 V 0 OO'l ZS6"6- S f "8 Wll 6L2 V 人 13 VO Z99L 隠 V C.600 / COO∑: df / X3d 0 08 "£ 200 * LH) 9'l- 106 '6 ιοε V 丄 VN 13 L68L W1V13H 3 9i' £ 2 00 Ί 12 2-09 £ -ε 9 ^ 6'0l ιοε v 1VN 9D 0681 W1V13H 3 96 ΊΖ 00 "I ifl- £ Ί 809'OL ιοε v 1VN 90 688L HiVi3H 3 οε'εζ oo Ί SL6'2- (1L92'6 ιοε ν 丄 VN 8881 W1V13H 3 88Έ2 00 Ί 2 '2-602' 8 ιοε ν 丄 VN £ 3 88L W1V13H 0 ・ ^ ΊΙ 00 "L S9 £ '0 ~ i L61 ιοε ν 丄 VN 10 988L H1V13H 3 Wll 00 Ί IS 0 16 £' 8 ιοε ν 1VN 23 9881 W1V13H 3 ES ' 6l OO'L L69 "0 16 '01 L9S6 ιοε ν 1VN L3 t ^ 88L HiVi3H 3 00” I 862 ”l 98 6 926 '8 ιοε ν iVN 3 9891 W1V13H N 68“ 02 00 ”l 689 * 0 890 '8 862 "6 ιοε ν 丄 VN N Z88L HiVi3H 0 ^ VZZ OO'l i'9l- 909 * 8 9i9" 8 \ ΖΖ ν ΝΊ3 0 f89L INOiV 0 Wll OO'l Zl6'9l- 201 · 8 622 "6 ν N13 3 E89L Oki VN n ~ u OO'L 16 '8 62' \ / ι ν ΝΠ3 Z3N Z89L W01V 0 98 * 82 OO'l izrsi- 262 '9 698 "£ l ΙΖΖ V N1D iao 1891 Hidden V 3 61 "2 OO'l SO U9 * £ L VIZ2 V ΝΊ3 0891 Odd V 0 68" 2 OO'l ISO '-SZ £ 71 V 2 V ΝΊ3 DO 6i9l Hidden V 0 ΐ ^ Ζ 00 "L' i OiO'U VL2Z V ΝΊ3 ao 8i9l hidden V 3 i 'u oo'i I20'9l- OS · 8 I96 "0l VI VN" ID o Z29L Oki VN οε'ιζ oo'i S6i'6 f8i "0l
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(9L <½)8攀 (9L <½) 8 climbs
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C.600/COOZdf/X3d 66 表 8(その 17) C.600 / COOZdf / X3d 66 Table 8 (Part 17)
ATOM 3578 C ALA B 221 43.688 19.150 15.005 1.00 25.15 C ATOM 3579 0 ALA B 221 43.024 19.100 16.045 1.00 25.46 0 ATOM 3580 N GLN B 221A 44.506 18.177 14.615 1.00 25.12 N ATOM 3581 CA GLN B 221A 44.703 16.964 15.407 1.00 25.43 C ATOM 3582 CB GLN B.221A 45.084 15.789 14.504 1.00 26.96 C ATOM 3583 CG GLN B 221A 44.100 14.654 14.515 1.00 29.67 c ATOM 3584 CD GLN B 221A 42.770 15.075 13.967 1.00 30.62 c ATOM 3585 0E1 GLN B 221A 42.649 15.371 12.781 1.00 32.84 0 ATOM 3586 NE2 GLN B 221A 41.761 15.123 14.824 1.00 30.92 N ATOM 3587 C GLN B 221A 45.822 17.171 16.430 1.00 24.48 c ATOM 3588 0 GLN B 221A 46.767 17.919 16.190 1.00 24.11 0 HETATM 3786 N NAT B 301 47.225 13.220 - 0.530 1.00 22.58 N HETATM 3787 C NAT B 301 47.210 14.309 -1.503 1.00 22.35 C HETATM 3788 CI NAT B 301 46.376 15.478 -0.999 1.00 21.48 C HETATM 3789 C2 NAT B 301 48.317 12.756 0.076 1.00 23.97 c HETATM 3790 01 NAT B 301 49.415 13.285 -0.194 1.00 23.27 0 HETATM 3791 C3 NAT B 301 49.535 8.939 .3.628 1.00 25.73 c HETATM 3792 C4 NAT B 301 48.687 8.036 4.284 1.00 26.00 c HETATM 3793 C5 NAT B 301 47.288 8.043 4.053 ■1.00 26.01 c HETATM 3794 C6 NAT B 301 46.701 8.954 3.155 1.00 25.68 c HETATM 3795 C7 NAT B 301 47.534 9.891 2.467 1.00 25.74 c HETATM 3796 C8 NAT B 301 48.948 9.860 2.723 1.00 26.19 c HETATM 3797 S9 NAT B 301 49.775 11.045 1.819 1.00 27.03 s HETATM 3798 CIO NAT B 301 48.251 11.615 1.069 1.00 25.10 c HETATM 3799 Cll AT B 301 47.139 10.950 1.469 1.00 24.83 c HETATM 3800 CI 3 NAT B 301 45.473 19.117 3.914 1.00 19.55 c HETATM 3801 CI 4 NAT B 301 45.009 18.512 2.599 1.00 19.88 c HETATM 3802 CI 5 NAT B 301 45.556 18.316 5.061 1.00 19.35 c HETATM 3803 C16 NAT B 301 45.989 18.856 6.271 1.00 19.35 c HETATM 3804 C17 NAT B 301 46.343 20.208 6.340 1.00 20.15 c HETATM 3805 CI 8 NAT B 301 46.816 20.810 7.662 1.00 20.09 c HETATM 3806 Nl AT B 301 45.776 20.863 8.691 1.00 20.85 N HETATM 3807 CI 9 NAT B 301 46.258 21.011 5.186 1.00 20.01 c 67 表 8(その 18) ATOM 3578 C ALA B 221 43.688 19.150 15.005 1.00 25.15 C ATOM 3579 0 ALA B 221 43.024 19.100 16.045 1.00 25.46 0 ATOM 3580 N GLN B 221A 44.506 18.177 14.615 1.00 25.12 N ATOM 3581 CA GLN B 221A 44.703 16.964 15.407 1.00 25.43 C CB GLN B.221A 45.084 15.789 14.504 1.00 26.96 C ATOM 3583 CG GLN B 221A 44.100 14.654 14.515 1.00 29.67 c ATOM 3584 CD GLN B 221A 42.770 15. GLN B 221A 41.761 15.123 14.824 1.00 30.92 N ATOM 3587 C GLN B 221A 45.822 17.171 16.430 1.00 24.48 c ATOM 3588 0 GLN B 221A 46.767 17.919 16.190 1.00 24.11 0 HETATM 3786 N NAT B 301 47.225 13.220-0.530 1.00 22.58 N HETATM 3787 B 301 47.210 14.309 -1.503 1.00 22.35 C HETATM 3788 CI NAT B 301 46.376 15.478 -0.999 1.00 21.48 C HETATM 3789 C2 NAT B 301 48.317 12.756 0.076 1.00 23.97 c HETATM 3790 01 NAT B 301 49.415 13.285 -0.194 1.00 23.27 0 HETATM 3791 C3 NAT B 301 49.535 8.939 .3.628 1.00 25.73 c HETATM 3792 C4 N AT B 301 48.687 8.036 4.284 1.00 26.00 c HETATM 3793 C5 NAT B 301 47.288 8.043 4.053 ■ 1.00 26.01 c HETATM 3794 C6 NAT B 301 46.701 8.954 3.155 1.00 25.68 c HETATM 3795 C7 NAT B 301 47.534 9.891 2.467 1.00 25.74 c HETATM 3796 C8 NAT B 301 48.948 9.860 2.723 1.00 26.19 c HETATM 3797 S9 NAT B 301 49.775 11.045 1.819 1.00 27.03 s HETATM 3798 CIO NAT B 301 48.251 11.615 1.069 1.00 25.10 c HETATM 3799 Cll AT B 301 47.139 10.950 1.469 1.00 24.83 c HETATM 3800 CI 3 NAT B 301 45.473 19.117 3.914 1.00 19.55 c HETATM 3801 CI 4 NAT B 301 45.009 18.512 2.599 1.00 19.88 c HETATM 3802 CI 5 NAT B 301 45.556 18.316 5.061 1.00 19.35 c HETATM 3803 C16 NAT B 301 45.989 18.856 6.271 1.00 19.35 c HETATM 3804 C17 NAT B 301 46.343 20.208 6.340 1.00 20.15 c HETATM 3805 CI 8 NAT B 301 46.816 20.810 7.662 1.00 20.09 c HETATM 3806 Nl AT B 301 45.776 20.863 8.691 1.00 20.85 N HETATM 3807 CI 9 NAT B 301 46.258 21.011 5.186 1.00 20.01 c 67 Table 8 (Part 18)
HETATM 3808 C20 NAT B 301 45.827 20.468 3.981 1.00 19.08 C HETATM 3809 C21 NAT B 301 46.005 17.455 2.121 1.00 21.05 C HETATM 3810 C22 NAT B 301 46.128 17.391 0.605 1.00 21.31 C HETATM 3811 N2 NAT B 301 46.949 16.232 0.165 1.00 21.19 N HETATM 3812 C23 NAT B 301 48.431 16.454 0.117 1.00 20.47 C HETATM 3813 CI ACY B 302 41.777 19.407 -1.558 1.00 21.67 C HETATM 3814 C2 ACY B 302 43.095 19.810 -0.909 1.00 22.77 C HETATM 3815 01 ACY B 302 44.174 19.309 -1.597 1.00 21.85 0 HETATM 3816 02 ACY B 302 43.174 20.513 0.111 1.00 22.86 0 ATOM 4158 N ALA C 56 54.787 -1.290 5.862 1.00 16.81 N ATOM 4159 CA ALA C 56 54.706 -0.386 6.997 1.00 16.36 C ATOM 4160 CB ALA C 56 55.977 0.454 7.096 1.00 16.28 C ATOM 4161 C ALA C 56 53.484 0.534 6.914 1.00 16.33 C ATOM 4162 0 ALA C 56 52.949 0.925 7.945 1.00〗5.63 0 ATOM 4163 N HIS C 57 53.038 0.883 5.707 1.00 16.27 N ATOM 4164 CA HIS C 57 51.894 1.794 5.607 1.00 16.41 C ATOM 4165 CB HIS C 57 51.739 2.348 4.187 1.00 15.35 C ATOM 4166 CG HIS C 57 51.035 1.425 3.240 1.00 15.08 C ATOM 4167 CD2 HIS C 57 49.728 .1.085 3.132 1.00 14.22 C ATOM 4168 ND1 HIS C 57 51.689 0.766 2.222 1.00 14.66 N ATOM 4169 CE1 HIS C 57 50.814 0.064 1.522 1.00 15.17 C ATOM 4170 NE2 HIS c 57 49.616 0.242 2.053 1.00 15.07 N ATOM 4171 C HIS c 57 50.597 1.137 6.063 1.00 16.30 C ATOM 4172 0 HIS c 57 49.587 1.807 6.263 1.00 17.10 0 ATOM 4173 N CYS c 58 50.624 -0.178 6.224 1.00 16.47 N ATOM 4174 CA CYS c CH 49.456 -0.896 6.697 1.00 16.68 C ATOM 4175 CB CYS c 58 49.567 -2.379 6.344 1.00 16.79 c ATOM 4176 SG CYS c 58 49.387 -2.761 4.573 1.00 17.36 s ATOM 4177 C CYS c 58 49.331 -0.750 8.211 1.00 17.15 c ATOM 4178 0 CYS c 58 48.223 -0.729 8.758 1.00 16.46 0 ATOM 4179 N VAL c 59 50.468 -0.644 8.890 1.00 17.44 N ATOM 4180 CA VAL c 59 50.469 -0.533 10.341 1.00 19.21 c ATOM 4181 CB VAL c 59 51.254 -1.706 10.976 1.00 19.37 c 0 S9'6L 00•I 909 "9 SO'Ll t^Z6'99 96 3 H人丄 203 oos W01VHETATM 3808 C20 NAT B 301 45.827 20.468 3.981 1.00 19.08 C HETATM 3809 C21 NAT B 301 46.005 17.455 2.121 1.00 21.05 C HETATM 3810 C22 NAT B 301 46.128 17.391 0.605 1.00 21.31 C HETATM 3811 N2 NAT B 301 46.949 16.232 0.165 1.00 21.19 N HETATM 38 C23 NAT B 301 48.431 16.454 0.117 1.00 20.47 C HETATM 3813 CI ACY B 302 41.777 19.407 -1.558 1.00 21.67 C HETATM 3814 C2 ACY B 302 43.095 19.810 -0.909 1.00 22.77 C HETATM 3815 01 ACY B 302 44.174 19.309 -1.597 1.00 21.85 0 HETATM 3816 02 ACY B 302 43.174 20.513 0.111 1.00 22.86 0 ATOM 4158 N ALA C 56 54.787 -1.290 5.862 1.00 16.81 N ATOM 4159 CA ALA C 56 54.706 -0.386 6.997 1.00 16.36 C ATOM 4160 CB ALA C 56 55.977 0.454 7.096 1.00 16.28 C ATOM 4161 C ALA C 56 53.484 0.534 6.914 1.00 16.33 C ATOM 4162 0 ALA C 56 52.949 0.925 7.945 1.00〗 5.63 0 ATOM 4163 N HIS C 57 53.038 0.883 5.707 1.00 16.27 N ATOM 4164 CA HIS C 57 51.894 1.794 5.607 1.00 16.41 C ATOM 4165 CB HIS C 57 51.739 2.348 4.187 1.00 15.35 C ATOM 4166 CG HIS C 57 51.035 1.425 3.240 1.00 15.08 C ATOM 4167 CD2 HIS C 57 49.728 .1.085 3.132 1.00 14.22 C ATOM 4168 ND1 HIS C 57 51.689 0.766 2.222 1.00 14.66 N ATOM 4169 CE1 HIS C 57 50.814 0.064 1.522 1.00 15.17 C ATOM 4170 NE2 HIS c 57 49.616 0.242 2.053 1.00 15.07 N ATOM 4171 C HIS c 57 50.597 1.137 6.063 1.00 16.30 C ATOM 4172 0 HIS c 57 49.587 1.807 6.263 1.00 17.10 0 ATOM 4173 N CYS c 58 50.624 -0.178 6.224 1.00 16.47 N ATOM 4174 CA CYS c CH 49.456 -0.896 6.697 1.00 16.68 C ATOM 4175 CB CYS c 58 49.567 -2.379 6.344 1.00 16.79 c ATOM 4176 SG CYS c 58 49.387 -2.761 4.573 1.00 17.36 s ATOM 4177 C CYS c 58 49.331 -0.750 8.211 1.00 17.15 c ATOM 4178 0 CYS c 58 48.223 -0.729 8.758 1.00 16.46 0 ATOM 4179 N VAL c 59 50.468 -0.644 8.890 1.00 17.44 N ATOM 4180 CA VAL c 59 50.469 -0.533 10.341 1.00 19.21 c ATOM 4181 CB VAL c 59 51.254 -1.706 10.976 1.00 19.37 c 0 S9'6L 00 • I 909 "9 SO'Ll t ^ Z6'99 96 3 H people 丄 203 oos W01V
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0 61 "81 00 ■I 06に 0 - 2£9'L- 961 0 yョ S DO 62£S 隱 V0 61 "81 00 ■ I 06 0-2 £ 9'L- 961 0 y S DO 62 £ S Oki V
0 ^ ί 00 •I 8·0 66 ·2- 6·8 961 0 BO 82£S 隠 V0 ^ ί 00 • I 80 66 2-6 6 961 0 BO 82 £ S Hidden V
0 9071 00 •I εεζ'ο 698'£- ίΠ'^ 96L d VO LZl^ H01V0 9071 00 • I εεζ'ο 698 '£-ίΠ' ^ 96L d VO LZl ^ H01V
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0 11 Ι 00 'I Ζ8 Ό- 89'S- Π. 3 dSV 3 隱 V0 11 Ι 00 'I Ζ8 Ό- 89'S- Π. 3 dSV 3 Oki V
0 Wll 00 •I £68 - £9£'9 - 08S 'St^ t^6l 0 dSV W01V0 Wll 00I £ 68-£ 9 £ '9-08S' St ^ t ^ 6l 0 dSV W01V
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0 9Γ91 00 Ί m •2S EL2 3 "1VA O 1 ^ 隠 V0 9Γ91 00 Ί m • 2S EL2 3 "1VA O 1 ^ hidden V
N 8Γ91 00 ,1 9'S- 99Γ£9 £L2 31ΥΛ N 09fr9 H01VN 8Γ91 00, 1 9'S- 99Γ £ 9 £ L2 31ΥΛ N 09fr9 H01V
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0 16 L 00' ■I £607- 9t7 '9 9L2 a DO 98SZ 隱 V0 16 L 00 '■ I £ 607-9t7' 9 9L2 a DO 98SZ Oki V
D 6 ■frl 00' Ί 629'9 Q 'Z- 061 912 a dill 93 mL 隱D 6 frl 00 'Ί 629'9 Q' Z- 061 912 a dill 93 mL Hidden
3 ZL ■ 00' Ί 602■£ - £667 S12 a da丄 O mL 隱 V3 ZL ■ 00 'Ί 602 ■ £-£ 667 S12 a da 丄 O mL Hidden V
N 90' L 00' Ί 61Γ9 6 S'fr- 0197 912 a N 28ε 隠 VN 90 'L 00' Ί 61Γ9 6 S'fr- 0197 912 a N 28ε hidden V
0 00' Ί 1769^- 88 8 IZ a Hョ s 0 L ■V0 00 'Ί 1769 ^-88 8 IZ a H ョ s 0 L ■ V
3 'ει 00' Ί 912"9- 60ΓΖ a 3 08ε 画3 'ει 00' Ί 912 "9-60ΓΖ a 3 08ε picture
0 99 •11 00' Ί 921 ' 90i"9- PIZ a Mョ s 30 6ζε 匿 V 0 99 • 11 00 'Ί 921' 90i "9-PIZ a M
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28 ΐ C.600/COOidf/X3d s £9'9Z 00•I ει 968 "£ Ζ697 10E α丄 VM 6S Lf9i 丄ョ H28 ΐ C.600 / COOidf / X3d s £ 9'9Z 00 • I ει 968 "£ Ζ697 10E α 丄 VM 6S Lf9i
3 19'92 00 "L ο·ε £82 '9 69f "8 ιοε α丄 VN 83 OHL 丄ョ H3 19'92 00 "L ο · ε £ 82 '9 69f" 8 ιοε α 丄 VN 83 OHL
0 £Z'S2 00 "l ·2 '9 6Ζ8·6 109 α丄 VN O 6£92 匪ョ H0 £ Z'S2 00 "l · 2 '9 6Ζ8 · 6 109 α 丄 VN O 6 £ 92 Marauder H
3 00 '92 00 •I οιε'ε ( •9 699'OL ιοε α丄 VN 93 8£9i W1V13H3 00 '92 00 • I οιε'ε (• 9 699'OL ιοε α 丄 VN 93 8 £ 9i W1V13H
0 66 ' Z 00 •I IP •Z StO'Ol ιοε α丄 VN S3 £9Z W丄 V丄ョ H0 66 'Z 00 • I IP • Z StO'Ol ιοε α 丄 VN S3 £ 9Z W 丄 V 丄 H
0 00 Ί 8£L LZ 'L 919'8 L0E α丄 VN to 9£9i W1V13H0 00 Ί 8 £ L LZ 'L 919'8 L0E α 丄 VN to 9 £ 9i W1V13H
D 00 •I 989 'ε οζε "9 818' ιοε α丄 Π 9£9Z W丄 V丄ョ HD 00 • I 989 'ε οζε "9 818' ιοε α 丄 Π 9 £ 9Z W 丄 V 丄 H
0 00 •I ιιο'ι ΖΟΐ •I εに 8 ιοε α丄 VN 10 L W1V13H0 00 • I ιιο'ι ΖΟΐ • Iε 8 ιοε α 丄 VN 10 L W1V13H
3 89 -£2 00 "L Z9L "l •I 612·6 ιοε α丄 ZO mi W1V13H3 89-£ 200 "L Z9L" l • I 612 · 6ιοε α 丄 ZO mi W1V13H
0 00 ■I 262 '0 oso •I- vw ιοε α丄 \/N 13 2£9i H1V13H0 00 ■ I 262 '0 oso • I- vw ιοε α 丄 \ / N 13 2 £ 9i H1V13H
0 00 Ί 900 "0 刚 ■0 82£'0L ιοε α丄 3 l£ L W1V13H0 00 Ί 900 "0 刚 ■ 0 82 £ '0L ιοε α 丄 3 l £ L W1V13H
N 00 Ί 969 "0 2SZ Ί 9l£'0l ιοε α 1VN N 0£9i W1V13HN 00 Ί 969 "0 2SZ Ί 9l £ '0l ιοε α 1VN N 0 £ 9i W1V13H
0 98" 00 'I 0L6 L 896 •0 09£'0L α M13 0 隨0 98 "00 'I 0L6 L 896 • 0 09 £' 0L α M13 0
0 00 Ί 281 '81 089 οιε'ΐι VI α ΝΊ3 3 i 隱 V0 00 Ί 281 '81 089 οιε'ΐι VI α ΝΊ3 3 i Oki V
N 99-οε 00' Ί 190'£L 008 'ε οεε'ει V12Z α ΝΊΟ 23N W01VN 99-οε 00 'Ί 190' £ L 008 'ε οεε'ει V12Z α ΝΊΟ 23N W01V
0 εζ·ιε 00' Ί Z6Z ιιι^ α HID 130 6 2 I/IOIV0 εζιε 00 'Ί Z6Z ιιι ^ α HID 130 6 2 I / IOIV
3 ^"62 00' Ί 丄 08 ■ε VI α N13 ao 8 i WOiV3 ^ "62 00 '丄 丄 08 ■ ε VI α N13 ao 8 i WOiV
0 99'Z2 00' Ί 611 '91 82S iZZ α ΝΊ3 93 LZPL W01V0 99'Z2 00 'Ί 611 '91 82S iZZ α ΝΊ3 93 LZPL W01V
3 9ε· 2 00' Ί 06 91 0Z9 'τ 89 '2L ϊΖΖ α N13 93 mi IN01V3 9ε2 00 'Ί 06 91 0Z9' τ 89 '2L ϊΖΖ α N13 93 mi IN01V
3 89 2 00' L 6f9 ■ι m'zi ΪΖΖ α N10 V3 WOIV3 89 2 00 'L 6f9 ■ ι m'zi ΪΖΖ α N10 V3 WOIV
N 09· 00' Ί Z8Z"9l 20£ ■0 VI α NID N ■VN 09 · 00 'Ί Z8Z "9l 20 £ ■ 0 VI α NID N ■ V
0 6 02 00' Ί 19£'8L ιοε ■0- 902 · ιζζ α V，V 0 mL WOIV0 6 02 00 'Ί 19 £' 8L ιοε ■ 0- 902 · ιζζ α V, V 0 mL WOIV
3 60Ί2 00' Ί U£ l •ο - 9£S"£l ιζζ α V1V 3 ZZVL WOIV3 60Ί2 00 'Ί U £ l • ο-9 £ S "£ l ιζζ α V1V 3 ZZVL WOIV
3 Z0-02 00' Ί 969 'Ζ- 998'fl ill α νιν 83 IZVl WOIV3 Z0-02 00 'Ί 969' Ζ- 998'fl ill α νιν 83 IZVl WOIV
3 99 '02 00' I S9 91 S26 Ί- 009'£l ill α νιν V3 mL WOiV3 99 '02 00 'I S9 91 S26 Ί- 009' £ llill α νιν V3 mL WOiV
N 20*12 00' I 60£'SL 166 "l- 199'£L ιζζ α VIV N WOIVN 20 * 12 00 'I 60 £' SL 166 "l- 199 '£ L ιζζ α VIV N WOIV
0 6 00' I 8LO'9l 2LS •0- οζζ α S人 3 0 8^ WOIV0 6 00 'I 8LO'9l 2LS • 0- οζζ α S 3 0 8 ^ WOIV
3 Ll' Z 00' I 692 •L- 022 α SAO D LIPL 隱 V3 Ll 'Z 00' I 692L-022 α SAO D LIPL Oki V
S IS' 00' I 86S"0l ZSl '2- QZZ α SAO DS 9 2 WOIVS IS '00' I 86S "0l ZSl '2- QZZ α SAO DS 9 2 WOIV
3 89"IZ 00' L 9 ·21 991 'τ- rSL QZZ α SAO 90 Slfi WOIV3 89 "IZ 00 'L 921 991' τ- rSL QZZ α SAO 90 Slfi WOIV
3 8'0Z 00" I 9 ο·ει ZIP Ί- E6ft7l οζζ α SAO VO 2 WOIV3 8'0Z 00 "I 9 ο · ει ZIP Ί- E6ft7l οζζ α SAO VO 2 WOIV
N 9L "02 00' I 9Ll"0- S80' 022 α SAO N ε 隱N 9L "02 00 'I 9Ll" 0- S80' 022 α SAO N ε
0 fr9"6l 00' I 19£ΊΙ 019 "0- 6 'Zl 612 α人 Ί3 0 WOIV 0 fr9 "6l 00 'I 19 £ ΊΙ 019" 0- 6'Zl 612 α person Ί3 0 WOIV
ε 8 xε 8 x
0/£00ZdT/13d 0 / £ 00ZdT / 13d
ireno/i-oor OAV 表 8(その 35) ireno / i-oor OAV Table 8 (Part 35)
HETATM 7642 C10 NAT D 301 9.249 3.219 1.858 1.00 25.01 C HETATM 7643 Cll AT D 301 10.337 3.991 2.120 1.00 24.27 C HETATM 7644 CI 3 NAT D 301 12.095 -3.250 6.408 1.00 16.12 C HETATM 7645 C14 NAT D 301 12.594 -2.985 4.994 1.00 17.19 C HETATM 7646 CI 5 NAT D 301 11.927 -2.182 7.298 1.00 16.33 C HETATM 7647 C16 NAT D 301 11.465 -2.404 8.599 1.00 15.81 C HETATM 7648 C17 NAT D 301 11.163 -3.705 9.022 1.00 15.91 C HETATM 7649 C18 NAT D 301 10.657 -3.949 10.448 1.00 15.92 C HETATM 7650 N1 NAT D 301 11.635 -3.622 11.490 1.00 6.93 N HETATM 7651 C19 NAT D 301 11.330 -4.785 8.128 1.00 16.19 C HETATM 7652 C20 NAT D 301 11.794 -4.557 6.825 1.00 15.78 C HETATM 7653 C21 NAT D 301 11.648 -2.037 4.244 1.00 19.80 C HETATM 7654 C22 NAT D 301 11.313 -2.515 2.834 1.00 20.45 C HETATM 7655 N2 NAT D 301 10.487 - 1.523 2.084 1.00 22.15 N HETATM 7656 C23 NAT D 301 9.014 -1.799 - 2.036 1.00 20.10 C HETATM 7657 C1 ACY D 302 15.666 -4.651 1.286 1.00 19.48 c HETATM 7658 C2 ACY D 302 14.251 -4.809 1.843 1.00 19.65 c HETATM 7659 01 ACY D 302 14.267 -5.369 3.090 1.00 19.16 0 HETATM 7660 02 ACY D 302 13.256 -4.785 1.130 1.00 20.16 0 HETATM 7661 0 HOH 401 10.122 27.481 -18.417 1.00 19.27 0 HETATM 7662 0 402 5.380 9.076 1.782 1.00 15.53 0 HETATM 7663 0 HOH 403 55.135 20.110 1.657 1.00 20.89 0 HETATM 7664 0 HOH 404 6.027 17.037 -12.811 1.00 23.09 0 HETATM 7665 0 HOH 405 9.395 -1.900 -8.790 1.00 29.70 0 HETATM 7666 0 HOH 406 43.005 28.428 0.610 1.00 8.62 0 HETATM 7667 0 HOH 407 59.021 6.711 4.315 1.00 22.84 0 HETATM 7668 0 HOH 408 -1.652 8.680 3.738 1.00 22.22 0 HETATM 7669 0 HOH 409 9.927 -8.832 -11.017 1.00 19.57 0 HETATM 7670 0 HOH 410' 70.595 -4.945 11.325 1.00 38.86 0 HETATM 7671 0 HOH 411 14.592 -13.156 5.699 1.00 18.65 0 HETATM 7672 0 HOH 412 65.936 -7.405 -5.324 1.00 24.25 0 HETATM 7673 0 HOH 413 7.053 17.475 12.259 1.00 20.30 0 HETATM 7674 0 HOH 414 1.808 23.260 -18.895 1.00 25.62 0 0 0·62 00 Ί £9ε·9 9£6'6l7 L H0H 0 LOU W1V13H 0 8fr'6L 00 Ί 'o- 9LZ'9
Figure imgf000186_0001
H0H 0 90 NIV13H 0 £9"0£ 00Ί sii ·ε 9Z0'9- 8Ζ9·69 m H0H 0 SO H1V1HH 0 S8'£2 OO'L 669 '9 9'6fr m ■ o u H1V13H 0 ε ' 12 οο'ι '\.z '9 - i H0H o εοζ W1V13H 0 GP'LZ 00 Ί 601 'lい 80 ' i H0H 0 ZQLL 隨丄ョ H 0 LO' Z 00 ·ι ·ιι 601 "91- S£0'£- i H0H 0 L0Z2 H1V13H 0 Ζ 'ΖΖ 00·1 '8- 668 '6 O H0H 0 0022 W1VI3H 0 f6'02 00 ·1 092 "fl 620Ό- 192ΊΙ m HOH 0 6692 W1V13H 0 88"6L 00 "I εοε·^ 868 - HOH 0 869 W丄 V丄ョ H 0 19-92 00 Ί 028 ·6 91 '9£ IS£"2 丄 ε HOH 0 Z69i 1N1V13H 0 92-82 00 Ί 899 "£L 6ΖΠ- 8 9 m HOH 0 969i W1V13H 0 00·2£ OO'L 96ΕΌ S66'll 88Z 9 9£f HOH 0 969Z W1V13H 0 εε;εζ οο'ι 918'i- 698 "9- ΠΡ HOH 0 ^L W1V13H 0 09 2 00 Ί
Figure imgf000186_0002
££f HOH 0 £69i W1V13H 0 6S'2Z ΟΟ'Ι 696' - 298 Ί Z£f HOH 0 W1V13H 0 Z£'92 00 "I 69L ·9 8Ζ6Ί 9 6 '0 - U HOH 0 1692 W丄 V丄ョ H 0 99*62 ΟΟ'Ι U0"9 092'Zt ZSO'09 0£f HOH 0 069Z W1V13H 0 00 Ί WO - ΠΙ'ΖΖ frL9'0Z m HOH 0 6891 WIV13H 0 09*02 00 Ί m'o HQ'l Z9Z*69 8 HOH 0 8892 W1V13H 0 ζθ'ΐε ΟΟΊ Zt'Z'Ol 'n HOH 0 L W1V13H 0 ΖΡΊί 00 "I 8£0"S- 619'i W6 - 9 HOH 0 9891 W1V13H 0 επζ οο'ι 'o- 9·εε '8 S HOH O 989Z W1V13H 0 ε 81 οο'ι 96Γ0- £2£"6- 681 '8f H HOH 0 mL W1V13H 0 Z6'8L ΟΟ'Ι 019 - 280 Ό m HOH 0 £892 W1V13H 0 9" Ζ 00 Ί 9Ζ8·£- S96'Sl 8t^0"89 Z HOH O 2892 W丄 V丄ョ H 0 iL'OZ OO'L ^*2 006 'S £90 '29 l HOH O L89Z W1V13H 0 ' SI OO'L ΐ6ε·ト 691 ΊΖ 09 ·6 0 HOH 0 089Z 隨丄ョ H 0 66 00 'I 06i"9l 2£9"Ll- 0 ·1- 6Lfr HOH 0 6え 9丄 H1V13H 0 fr"8L OO'L ·ε- H'U 980 L 8 HOH 0 8え 9丄 隱丄ョ H 0 89*02 OO'L 016'6 OZZ'OL- 0Sfr"0Z LI HOH 0 LL9L H1V13H 0 Z£'9L OO'l 968'L- 088 "0- 9lf HOH 0 9え 9丄 W1V13H 0 ZVU OO'l £9871 ltZ"St- HOH 0 9Z9Z W1V13H θε 0) ） 8拏 HETATM 7642 C10 NAT D 301 9.249 3.219 1.858 1.00 25.01 C HETATM 7643 Cll AT D 301 10.337 3.991 2.120 1.00 24.27 C HETATM 7644 CI 3 NAT D 301 12.095 -3.250 6.408 1.00 16.12 C HETATM 7645 C14 NAT D 301 12.594 -2.985 4.994 1.00 17.19 C HETATM 7646 CI 5 NAT D 301 11.927 -2.182 7.298 1.00 16.33 C HETATM 7647 C16 NAT D 301 11.465 -2.404 8.599 1.00 15.81 C HETATM 7648 C17 NAT D 301 11.163 -3.705 9.022 1.00 15.91 C HETATM 7649 C18 NAT D 301 10.657 -3.949 10.448 1.00 15.92 C HETATM 7650 N1 NAT D 301 11.635 -3.622 11.490 1.00 6.93 N HETATM 7651 C19 NAT D 301 11.330 -4.785 8.128 1.00 16.19 C HETATM 7652 C20 NAT D 301 11.794 -4.557 6.825 1.00 15.78 C HETATM 7653 C21 NAT D 301 11.648 -2.037 4.244 1.00 19.80 C HETATM 7654 C22 NAT D 301 11.313 -2.515 2.834 1.00 20.45 C HETATM 7655 N2 NAT D 301 10.487-1.523 2.084 1.00 22.15 N HETATM 7656 C23 NAT D 301 9.014 -1.799-2.036 1.00 20.10 C HETATM 7657 C1 ACY D 302 15.666 -4.651 1.286 1.00 19.48 c HETATM 7658 C2 ACY D 302 14.251 -4.809 1.843 1.00 19.65 c HETATM 7659 01 ACY D 302 14.267 -5.369 3.090 1.00 19.16 0 HETATM 7660 02 ACY D 302 13.256 -4.785 1.130 1.00 20.16 0 HETATM 7661 0 HOH 401 10.122 27.481 -18.417 1.00 19.27 0 HETATM 7662 0 402 5.380 9.076 1.782 1.00 15.53 0 HETATM 7663 0 HOH 403 55.135 20.110 1.657 1.00 20.89 0 HETATM 7664 0 HOH 404 6.027 17.037 -12.811 1.00 23.09 0 HETATM 7665 0 HOH 405 9.395 -1.900 -8.790 1.00 29.70 0 HETATM 7666 0 HOH 406 43.005 28.428 0.610 1.00 8.62 0 HETATM 7667 59.021 6.711 4.315 1.00 22.84 0 HETATM 7668 0 HOH 408 -1.652 8.680 3.738 1.00 22.22 0 HETATM 7669 0 HOH 409 9.927 -8.832 -11.017 1.00 19.57 0 HETATM 7670 0 HOH 410 '70.595 -4.945 11.325 1.00 38.86 0 HETATM 7671 0 HOH 411 14.592 -13.156 5.699 1.00 18.65 0 HETATM 7672 0 HOH 412 65.936 -7.405 -5.324 1.00 24.25 0 HETATM 7673 0 HOH 413 7.053 17.475 12.259 1.00 20.30 0 HETATM 7674 0 HOH 414 1.808 23.260 -18.895 1.00 25.62 0 0 062 00 Ί £ 9ε9 9 £ 6'6l7 L H0H 0 LOU W1V13H 0 8fr'6L 00 Ί 'o- 9LZ'9
Figure imgf000186_0001
H0H 0 90 NIV13H 0 £ 9 "0 £ 00Ίsii · ε 9Z0'9- 8Ζ969 m H0H 0 SO H1V1HH 0 S8 '£ 2 OO'L 669' 9 9'6fr m ■ ou H1V13H 0 ε '12 οο ' ι '\ .z' 9-i H0H o εοζ W1V13H 0 GP'LZ 00 601 601 ll 80 i i H0H 0 ZQLL H H H 0 LO 'Z 00 ιιιι 601 "91- S £ 0' £-i H0H 0 L0Z2 H1V13H 0 Ζ 'ΖΖ 00 · 1'8- 668' 6 O H0H 0 0022 W1VI3H 0 f6'02 001 092 "fl 620Ό- 192ΊΙ m HOH 0 6692 W1V13H 0 88" 6L 00 "I εοε ^ 868-HOH 0 869 W 丄 V 丄 H 0 19-92 00 Ί 028 691 '9 £ IS £ "2 丄 ε HOH 0 Z69i 1N1V13H 0 92-82 00 Ί 899" £ L 6ΖΠ-8 9 m HOH 0 969i W1V13H 0 002 £ OO'L 96ΕΌ S66'll 88Z 9 9 £ f HOH 0 969Z W1V13H 0 εε ; εζ οο'ι 918'i- 698 "9- ΠΡ HOH 0 ^ L W1V13H 0 09 2 00 Ί
Figure imgf000186_0002
££ f HOH 0 £ 69i W1V13H 0 6S'2Z ΟΟ'Ι 696 '-298 Ί Z £ f HOH 0 W1V13H 0 Z £ '92 00 "I 69L9 8Ζ6Ί 9 6' 0-U HOH 0 1692 W 丄 V H H 0 99 * 62 ΟΟ'Ι U0 "9 092'Zt ZSO'09 0 £ f HOH 0 069Z W1V13H 0 00 Ί WO-ΠΙ'ΖΖ frL9'0Z m HOH 0 6891 WIV13H 0 09 * 02 00 Ί m ' o HQ'l Z9Z * 69 8 HOH 0 8892 W1V13H 0 ζθ'ΐε ΟΟΊ Zt'Z'Ol 'n HOH 0 L W1V13H 0 ΖΡΊί 00 "I 8 £ 0"S-619'i W6-9 HOH 0 9891 W1V13H 0 επζ οο'ι 'o- 9εε' 8 S HOH O 989Z W1V13H 0 ε 81 οο'ι 96Γ0- £ 2 £ "6- 681 '8f H HOH 0 mL W1V13H 0 Z6'8L ΟΟ'Ι 019-280 280 m HOH 0 £ 892 W1V13H 0 9 "Ζ 00 Ί 9Ζ8 · -S96'Sl 8t ^ 0" 89 Z HOH O 2892 W 丄 V 丄 H 0 iL'OZ OO'L ^ * 2 006 'S £ 90' 29 l HOH O L89Z W1V13H 0 'SI OO'L ΐ6ε · 691 ΊΖ 09 · 6 0 HOH 0 089Z Optional H 0 66 00' I 06i "9l 2 £ 9" Ll-0 · 1-6Lfr HOH 0 6 E 9 丄 H1V13H 0 fr "8L OO'L · ε- H'U 980 L 8 HOH 0 8 8 9 丄 Oki H 0 89 * 02 OO'L 016'6 OZZ'OL- 0Sfr" 0Z LI HOH 0 LL9L H1V13H 0 Z £ '9L OO'l 968'L-088 "0-9lf HOH 0 9 eh 9 丄 W1V13H 0 ZVU OO'l £ 9871 ltZ" S t-HOH 0 9Z9Z W1V13H θε 0)) 8 Halla
S 8 C.600/COOidf/X3d S 8 C.600 / COOidf / X3d
雕 OOZ ΟΛ\ 0 n•ιε 00Ί 6Z0'S- 192 '6L 08 HOH 0 丄ョ HSculpture OOZ ΟΛ \ 0 n • ιε 00Ί 6Z0'S- 192 '6L 08 HOH 0 丄 H
0 88 ■n 00· I 021 Ό- 909 2 6 fr 圆 0 6£Z W1V13H0 88 ■ n 00I 021 Ό-909 2 6 fr 圆 0 6 £ Z W1V13H
0 09 '02 00 Ί ZL9'8l- 21S'£- 606 Ί 8^ HOH 0 8ε" HIV丄ョ H0 09 '02 00 Ί ZL9'8l- 21S '£-606 Ί 8 ^ HOH 0 8ε "HIV
0 19 •82 00Ί 9 £'f- 6S9' ειε'ι- 2Zf HOH 0 LILL v丄ョ H0 19 • 82 00Ί 9 £ 'f-6S9' ειε'ι- 2Zf HOH 0 LILL v 丄 H
0 11 •ιε 00· I 909 L 686 "IS 9it^ HOH 0 9£ZZ 丄ョ H0 11 • ιε 00 · I 909 L 686 "IS 9it ^ HOH 0 9 £ ZZ
0 16·0 OO'l LIZ'O- 9it^ HOH 0 SEZ1 IN1V13H0 16 ・ 0 OO'l LIZ'O- 9it ^ HOH 0 SEZ1 IN1V13H
0 12 ·2ε OO'L εο ' s 229 ·9 - OU'82 PLP HOH 0 niL 丄ョ H0 12 · 2ε OO'L εο 's 229 · 9-OU'82 PLP HOH 0 niL
0 ιζ OO'L £8£"0 998 ' iL HOH 0 W丄 V丄ョ H0 ιζ OO'L £ 8 £ "0 998 'iL HOH 0 W 丄 V 丄 H
0 00 ■QZ OO'L 290 '9- 921 "6- ZL HOH 0 ULL WIV丄ョ H0 00 ■ QZ OO'L 290 '9-921 "6- ZL HOH 0 ULL WIV
0 80 •02 OO'l 228 '8- 219 2 Z92 'SI IL^ HOH 0 ILL W1V13H0 80 • 02 OO'l 228 '8- 219 2 Z92' SI IL ^ HOH 0 ILL W1V13H
0 LQ 'ττ OO'L 109 '6 ^99 1 868 Ό- QLP HOH 0 οεζζ W1V13H0 LQ 'ττ OO'L 109' 6 ^ 99 1 868 Ό- QLP HOH 0 οεζζ W1V13H
0 60 •ii OO'l 900 "i- 989 ^1- 9i8"12 69t7 HOH 0 ^ZLL H1V13H0 60 • ii OO'l 900 "i- 989 ^ 1-9i8" 12 69t7 HOH 0 ^ ZLL H1V13H
0 ZS ■ιε OO'l £66 Ό Of9'8l 18 ' 19 89 HOH 0 2ZLL H1V13H0 ZS ■ ιε OO'l £ 66 Ό Of9'8l 18 '19 89 HOH 0 2ZLL H1V13H
0 01 OO'l 8iS'£- l£L '29 HOH 0 LILL W1V13H0 01 OO'l 8iS '£-l £ L '29 HOH 0 LILL W1V13H
0 i OO'l 69 ·ε2- 0^8 " 1 HOH 0 mi 1N1V13H0 i OO'l 69E2-0 ^ 8 "1 HOH 0 mi 1N1V13H
0 91 •u OO'l WSl - 02671 29 2 S917 HOH 0 W1V13H0 91 • u OO'l WSl-02671 29 2 S917 HOH 0 W1V13H
0 08 •ii OO'l %ίΖ - 090 S89*ZS HOH 0 mi lUV丄ョ H0 08 • ii OO'l% ίΖ-090 S89 * ZS HOH 0 mi lUV 丄 H
0 6 W OO'L 9If '81 L90"lt7 HOH 0 Ull HIV丄ョ H0 6 W OO'L 9If '81 L90 "lt7 HOH 0 Ull HIV
0 ez '62 OO'l 11 - 6^9 ·οε HOH 0 ULl W1V13H0 ez '62 OO'l 11-6 ^ 9oε HOH 0 ULl W1V13H
0 l ·9Ζ OO'l 829'L- Z90 - HOH 0 ίΖίί W1V13H0 l9Ζ OO'l 829'L- Z90-HOH 0ίΖίί W1V13H
0 LL •12 OO'l 900 'LI 0^*81- 09 HOH 0 ULL H1V13H0 LL • 12 OO'l 900 'LI 0 ^ * 81- 09 HOH 0 ULL H1V13H
0 00" I 899*8- 092·εΐ- 608 - 6 t7 HOH 0 6UZ IN1V13H0 00 "I 899 * 8- 092 ・ εΐ- 608-6 t7 HOH 06 UZ IN1V13H
0 60 -n OO'l 8S HOH 0 8UZ W1V13H0 60 -n OO'l 8S HOH 0 8UZ W1V13H
0 £S'62 OO'l 899 Ό- εζο" 9εε·ε9 Z9f HOH 0 LILL WiViHH0 £ S'62 OO'l 899 Ό- εζο "9εε · ε9 Z9f HOH 0 LILL WiViHH
0 I 'iZ OO'L 18671- 929 "6 68S "6 9 HOH 0 9 W1V13H0 I 'iZ OO'L 18671- 929 "6 68S" 6 9 HOH 0 9 W1V13H
0 LL OO'l OfO'll- 98ΖΌΙ 98 Sfr HOH 0 912Z W1V13H0 LL OO'l OfO'll- 98ΖΌΙ 98 Sfr HOH 0 912Z W1V13H
0 S6 2 OO'l 90 9L 126 "9- 0 12 HOH 0 " HIV13H0 S6 2 OO'l 90 9L 126 "9- 0 12 HOH 0" HIV13H
0 80 "92 00*1 886 "6- S8に S - L6 'L9 HOH 0 ειζζ W丄 V丄ョ H0 80 "92 00 * 1 886" 6- S8 to S-L6 'L9 HOH 0 ειζζ W 丄 V 丄 H
0 99 '92 OO'l οοε'οι 19Z"£S HOH 0 Ζϊίί W1V13H0 99 '92 OO'l οοε'οι 19Z "£ S HOH 0 Ζϊίί W1V13H
0 00· I 916·1- 9'6 l HOH 0 ULL INIV13H0 00I 9161-9'6 l HOH 0 ULL INIV13H
0 OS 2 OO'l 11 HOH 0 OLiZ W1V13H0 OS 2 OO'l 11 HOH 0 OLiZ W1V13H
0 zru OO'l 809 "91 οε ·ε- οοε"θΐ 6^ HOH 0 60" W1V13H0 zru OO'l 809 "91 οε · ε- οοε" θΐ 6 ^ HOH 0 60 "W1V13H
0 0672 OO'L 6ΚΌΙ 8^ HOH 0 OLL W1V13H 0 0672 OO'L 6ΚΌΙ 8 ^ HOH 0 OLL W1V13H
98 I98 I
fZ.600/C003df/X3<I 0 99'62 00 Ί £99' 699 Ό- 丄 I6'8l CL9 HOH 0 ULL NiViHH 0 £9 "92 00" I IS ' 91 £6l'0L 0^6 ' L- 219 HOH 0 ULL H1V13H 0 E 00 Ί 086 f89'9- 115 HOH 0 iLLi H1V13H 0 22'9£ 00 Ί 169-9 V 0L9 HOH 0 ULL W1V13H 0 Ζ^ΊΖ 00 209'ΖΙ 9£8'£ 609 HOH 0 69Z IIUV丄ョ H 0 92 "92 ΟΟ'Ι 289^ 209· ε 9ZZ'Zl 80S HOH 0 89Z W1V13H 0 t^" £ 00 ·1 9 6·ε - ε S'Z£ ZOS HOH 0 9ZZ W1V13H 0 LZ'IZ 00 Ί 688 "92 εο ·οι 90S HOH 0 99ZZ Wi'Vi3H 0 06 00 Ί 816ΌΙ 98S"8L S09'9- 90S HOH 0 S9ZZ W丄 V丄ョ H 0
Figure imgf000188_0001
HOH o na 丄ョ H 0 η'ίζ ΟΟΊ "9'9L %[f'LZ- UVl\ £09 HOH 0 £921 W1V13H 0 L0 ε οο'ι 9i0'0- 9927- 209 HOH 0 29" W1V13H 0 ΠΊ^ 00 Ί Z0Z 1 296 Ζ- n 109 HOH 0 19" W1V13H 0 9·6Ζ 00·1 699 -9 £26'9l Z99"8E 009 HOH 0 09 Z W丄 V丄ョ H 0 98 "82 00·1 n%'L 990 "82 66 HOH 0 691Z t V丄ョ H 0 9ΐ -ζε οο'ι Ζ2ΖΊ- Z89'6 £20 '9- HOH 0 8SI W1V13H 0 190 ·2- m^i 208 'OS m HOH 0 1911 W1V13H 0 86 '8 00 "I ' - 9Ζ0Ί £66 '8 96f^ HOH 0 9SZZ N1V13H 0 οο· ι 600'EL- HL^Z 10 ' 09 96^ HOH 0 N1V13H 0 02 ΌΕ 00· I 99 W 180 '9 ZZ6" HOH 0 ^LL IN丄 V丄ョ H 0 19'82 00' I 【 UVLl 080 '2£ S6 HOH 0 £9ZZ IIUV丄ョ H 0 ζο'εε οο Ί LLl ' 290 '9 £69'99 HOH 0 W1V13H 0 0 ^2 00 'I 9£9'£- 008 "99 I 6 HOH 0 19Z1 W1V13H 0 88.61 00 Ί £2071 06 HOH 0 09ii. W1V13H 0 6Ζ*92 ΟΟ £26 "0- 1^9 9 m HOH 0 ^LL W1V13H 0 6£ '92 00"1 9017 226 "02 88 HOH 0 8 " W1V13H 0 0£'Ζ2 00 Ί 16ΖΌ m HOH 0 L U W1V13H 0 丄 8 '61 00 ·1 6 ·6 269'9L- £06*0- 98f HOH 0 9 " N1V13H 0 09·82 00 "I £0872- 8f HOH o W1V13H 0 8£ '81 OO'L 6L9"0 112*6- Mfr HOH o a H1V13H 0 £8·61 οο'ι 898·1 -
Figure imgf000188_0002
W1V13H 0 οε · ζ οο Ί ·8- 6·6 606· I Z HOH 0 lUL 丄ョ H 0 18·61 004 2ΐε ι 20 1- fZ "6 m HOH o i z H1V13H fZ.600 / C003df / X3 <I 0 99'62 00 Ί £ 99 '699 Ό- 丄 I6'8l CL9 HOH 0 ULL NiViHH 0 £ 9 "92 00" I IS '91 £ 6l'0L 0 ^ 6' L- 219 HOH 0 ULL H1V13H 0 E 00 Ί 086 f89'9- 115 HOH 0 iLLi H1V13H 0 22'9 £ 00 Ί 169-9 V 0L9 HOH 0 ULL W1V13H 0 Ζ ^ ΊΖ 00 209'ΖΙ 9 £ 8 '£ 609 HOH 0 69Z IIUV "92 ΟΟ'Ι 289 ^ 209 · ε 9ZZ'Zl 80S HOH 0 89Z W1V13H 0 t ^" £ 001 96 6 ε-ε S'Z £ ZOS HOH 0 9ZZ W1V13H 0 LZ'IZ 00 Ί 688 "92 εο · οι 90S HOH 0 99ZZ Wi'Vi3H 0 06 00 Ί 816ΌΙ 98S "8L S09'9- 90S HOH 0 S9ZZ W 丄 V 丄 H0
Figure imgf000188_0001
HOH o na 丄 H H 0 η'ΟΟΊ ΟΟΊ "9'9L% [f'LZ- UVl \ £ 09 HOH 0 £ 921 W1V13H 0 L0 ε οο'ι 9i0'0- 9927- 209 HOH 0 29" W1V13H 0 ΠΊ ^ 00 Ί Z0Z 1 296 Ζ- n 109 HOH 0 19 "W1V13H 0 9.6 Ζ 00 1 699 -9 £ 26'9l Z99" 8E 009 HOH 009 ZW 丄 V % 'L 990 "82 66 HOH 0 691Z t V 丄 H 0 9ΐ -ζε οο'ι Ζ2ΖΊ- Z89'6 £ 20' 9- HOH 0 8SI W1V13H 0 190 · 2-m ^ i 208 'OS m HOH 0 1911 W1V13H 0 86 '8 00 "I'-9Ζ0Ί £ 66 '8 96f ^ HOH 0 9SZZ N1V13H 0 οο ι 600'EL- HL ^ Z 10' 09 96 ^ HOH 0 N1V13H 0 02 ΌΕ 00I 99 W 180 '9 ZZ6 "HOH 0 ^ LL IN 丄 V 丄 H 0 19'82 00' I [UVLl 080 '2 £ S6 HOH 0 £ 9ZZ II UV 丄 H 0 0 ζο'εε οο Ί LLl' 290 '9 £ 69' 99 HOH 0 W1V13H 0 0 ^ 2 00 'I 9 £ 9' £-008 "99 I 6 HOH 0 19Z1 W1V13H 0 88.61 00 Ί £ 2071 06 HOH 0 09ii.W1V13H 0 6Ζ * 92 ΟΟ £ 26" 0- 1 ^ 9 9 m HOH 0 ^ LL W1V13H 0 6 £ '92 00 "1 9017 226" 02 88 HOH 0 8 "W1V13H 0 0 £ 'Ζ2 00 Ί 16ΖΌ m HOH 0 LU W1V13H 0 丄 8 '61 00 269'9L- £ 06 * 0- 98f HOH 0 9 "N1V13H 0 0982 00" I £ 0872- 8f HOH o W1V13H 0 8 £ '81 OO'L 6L9 "0 112 * 6- Mfr HOH oa H1V13H 0 £ 8 · 61 οο'ι 8981-
Figure imgf000188_0002
W1V13H 0 οε ζ οο Ί8-6.6 606 IZ HOH 0 lUL H0 181.81 004 2 ε ι 20 1-fZ "6 m HOH oiz H1V13H
(890^)8 ^ (890 ^) 8 ^
L 8 T L 8 T
C.600/£OOZdT/X3d 88 表 8(その 39) C.600 / £ OOZdT / X3d 88 Table 8 (part 39)
HETATM 7774 0 HOH 514 -0.420 -7.811 15.143 1.00 30.83 0 HETATM 7775 0 HOH 515 71.437 -8.550 1.874 1.00 33.73 0 HETATM 7776 0 HOH 516 8.798 -7.156 9.625 1.00 28.22 0 HETATM 7777 0 HOH 517 53.546 11.163 12.252 1.00 29.11 0 HETATM 7778 0 HOH 518 29.610 33.100 8.534 1.00 44.33 0 HETATM 7779 0 HOH 519 54.991 -3.374 19.266 1.00 17.62 0 HETATM 7780 0 HOH 520 50.271 -0.166 -15.557 1.00 30.76 0 HETATM 7781 0 HOH 521 58.531 31.633 3.675 1.00 27. Π 0 HETATM 7782 0 HOH 522 -8.277 20.504 -9.137 1.00 25.61 0 HETATM 7783 0 HOH 523 12.862 20.415 -19.658 1.00 32.73 0 HETATM 7784 0 HOH 524 8.664 -16.052 3.453 1.00 23.31 0 HETATM 7785 0 HOH 525 8.963 -1.921 -4.200 1.00 25.38 0 HETATM 7786 0 HOH 526 15.102 17.541 - 19.148 1.00 23.22 0 HETATM 7787 0 HOH 527 45.187 35.406 3.125 1.00 30.02 0 HETATM 7788 0 HOH 528 15.087 -23.961 -10.391 1.00 24.69 0 HETATM 7789 0 HOH 529 54.485 -9.847 2.263 1.00 23.55 0 HETATM 7790 0 HOH 530 -6.738 26.184 14.638 1.00 34.65 0 HETATM 7791 0 HOH 531 5.631 28.559 -8.138 1.00 21.96 0 HETATM 7792 0 HOH 532 36.045 -7.045 -0.383 1.00 30.98 0 HETATM 7793 0 HOH 533 -5.399 -4.104 11.424 1.00 24.84 0 HETATM 7794 0 HOH 534 -13.733 25.326 1.607 1.00 35.23 0 HETATM 7795 0 HOH 535 61.928 - 3.213 -10.738 1.00 25.81 0 HETATM 7796 0 HOH 536 35.138 - 11.196 12.578 1.00 21.60 0 HETATM 7797 0 HOH 537 23.314 25.794 -10.179 1.00 27.29 0 HETATM 7798 0 HOH 538 47.816 -14.467 -14.243 1.00 28.48 0 HETATM 7799 0 HOH 539 19.299 22.133 - 14.166 1.00 25.82 0 HETATM 7800 0 HOH 540 15.508 -16.835 -12.894 1.00 25.06 0 HETATM 7801 0 HOH 541 47.939 18.719 10.179 1.00 24.51 0 HETATM 7802 0 HOH 542 7.470 -15.087 20.490 1.00 25.72 0 HETATM 7803 0 HOH 543 51.296 -0.330 20.132 1.00 26.55 0 HETATM 7804 0 HOH 544 44.666 12.123 -0.228 1.00 28.42 0 HETATM 7805 0 HOH 545 48.184 14.372 -10.473 1.00 36.49 0 HETATM 7806 0 HOH 546 46.864 -1.107 11.224 1.00 32.84 0 0 6に 00•ι 69 ·ει Z60'£- 619 HOH 0 6E8Z W1V13HHETATM 7774 0 HOH 514 -0.420 -7.811 15.143 1.00 30.83 0 HETATM 7775 0 HOH 515 71.437 -8.550 1.874 1.00 33.73 0 HETATM 7776 0 HOH 516 8.798 -7.156 9.625 1.00 28.22 0 HETATM 7777 0 HOH 517 53.546 11.163 12.252 1.00 29.778 0 HETATM 0 HOH 518 29.610 33.100 8.534 1.00 44.33 0 HETATM 7779 0 HOH 519 54.991 -3.374 19.266 1.00 17.62 0 HETATM 7780 0 HOH 520 50.271 -0.166 -15.557 1.00 30.76 0 HETATM 7781 0 HOH 521 58.531 31.633 3.675 1.00 27.Π 0 HETATM 77 HOH 522 -8.277 20.504 -9.137 1.00 25.61 0 HETATM 7783 0 HOH 523 12.862 20.415 -19.658 1.00 32.73 0 HETATM 7784 0 HOH 524 8.664 -16.052 3.453 1.00 23.31 0 HETATM 7785 0 HOH 525 8.963 -1.921 -4.200 1.00 25.38 0HE HOH 526 15.102 17.541-19.148 1.00 23.22 0 HETATM 7787 0 HOH 527 45.187 35.406 3.125 1.00 30.02 0 HETATM 7788 0 HOH 528 15.087 -23.961 -10.391 1.00 24.69 0 HETATM 7789 0 HOH 529 54.485 -9.847 2.263 1.00 23.55 0 HETATM 7790 -6.738 26.184 14.638 1.00 34.65 0 HETATM 7791 0 HOH 531 5.631 28.559 -8.138 1.00 21. 96 0 HETATM 7792 0 HOH 532 36.045 -7.045 -0.383 1.00 30.98 0 HETATM 7793 0 HOH 533 -5.399 -4.104 11.424 1.00 24.84 0 HETATM 7794 0 HOH 534 -13.733 25.326 1.607 1.00 35.23 0 HETATM 7795 0 HOH 535 61.928-3.213 -10.838 1.00 25.81 0 HETATM 7796 0 HOH 536 35.138-11.196 12.578 1.00 21.60 0 HETATM 7797 0 HOH 537 23.314 25.794 -10.179 1.00 27.29 0 HETATM 7798 0 HOH 538 47.816 -14.467 -14.243 1.00 28.48 0 HETATM 7799 0 HOH 539 19.299 22.133 25.82 0 HETATM 7800 0 HOH 540 15.508 -16.835 -12.894 1.00 25.06 0 HETATM 7801 0 HOH 541 47.939 18.719 10.179 1.00 24.51 0 HETATM 7802 0 HOH 542 7.470 -15.087 20.490 1.00 25.72 0 HETATM 7803 0 HOH 543 51.296 -0.330 20.132 HETATM 7804 0 HOH 544 44.666 12.123 -0.228 1.00 28.42 0 HETATM 7805 0 HOH 545 48.184 14.372 -10.473 1.00 36.49 0 HETATM 7806 0 HOH 546 46.864 -1.107 11.224 1.00 32.84 0 0 6 to 00 • ι 69Epsilon Z60 '£-619 HOH 0 6E8Z W1V13H
0 E8"0£ 00 •ι UZ^ 288 ' 2- 09 ·1 8Ζ9 H0H 0 8£8i H1V13H0 E8 "0 £ 00 • ι UZ ^ 288 '2- 09 · 1 8Ζ9 H0H 0 8 £ 8i H1V13H
0 26'εε 00 ■ι Z69"9 W\l £09"09 ΖΖ9 HOH 0 Z£8Z W1V13H0 26'εε 00 ■ ι Z69 "9 W \ l £ 09" 09 ΖΖ9 HOH 0 Z £ 8Z W1V13H
0 99*82 00 •ι Zi9"Zl ·81 699·1 - 9Ζ9 HOH 0 9E8 H1V13H0 99 * 82 00 • ι Zi9 "Zl81 6991-9Ζ9 HOH 0 9E8 H1V13H
0 88 ε 00 •ι III 71 99l7'Sl- 9£9"9£ 9Ζ9 HOH 0 9£8Z W1V13H0 88 ε 00 • ι III 71 99l7'Sl- 9 £ 9 "9 £ 9Ζ9 HOH 0 9 £ 8Z W1V13H
0 00 Ί S'S- 2197£ Ζ06· ι^ HOH 0 H L W1V13H0 00 Ί S'S- 2197 £ Ζ06 · ι ^ HOH 0 H L W1V13H
0 ΐ -ιε 00 ■ι Ot^'ll- EZS HOH 0 £98Z W1V13H0 ΐ -ιε 00 ■ ι Ot ^ 'll- EZS HOH 0 £ 98Z W1V13H
0 6に ιε 00 ■ι ZOL ·6 Ζ19·9 22S HOH 0 Z L W1V13H0 6 to ιε 00 ■ ι ZOL · 6 Ζ19 · 9 22S HOH 0 Z L W1V13H
0 00 998 "£ ·0 12S HOH 0 LE82 W1V13H0 00 998 "£ · 0 12S HOH 0 LE82 W1V13H
0 ζι ~η 00 εεζ"οι- 96 · 029 HOH O i W1V13H0 ζι ~ η 00 εεζ "οι- 96 · 029 HOH O i W1V13H
0 ·8ε 00 "1 06S 19 - oirsz 69S HOH 0 6282 W丄 V丄ョ Η0 · 8ε 00 "1 06S 19-oirsz 69S HOH 0 6282 W 丄 V 丄 Η
0 00 •ι 960 -ζε 8ZS'6 895 HOH 0 8282 W1V13H0 00 • ι 960 -ζε 8ZS'6 895 HOH 0 8282 W1V13H
0 00 •ι m-z- 961 ·02 Ζ18·8ε Z9S HOH 0 Z28Z W1V13H0 00 • ι m-z- 961 02 Ζ18.8ε Z9S HOH 0 Z28Z W1V13H
0 •ι 9£0'0- ζε '99 99S HOH 0 9282 W1V13H0 • ι 9 £ 0'0- ζε '99 99S HOH 0 9282 W1V13H
0 SLOE 00' Ί ££8'6 2ίに 11 260 "8 99S HOH 0 S28Z W1V13H0 SLOE 00 'Ί ££ 8'6 2ί 11 260 "8 99S HOH 0 S28Z W1V13H
0 ' 8ε οο■ 'ι 0'LI εεο'92 629 " 9 9S HOH 0 Π 1 隨丄ョ Η0 '8ε οο ■' ι 0'LI εεο'92 629 "9 9S HOH 0 Π 1 丄
0 001 'ι U9"02- 919'91 £93 HOH 0 ΐΖ2ί 丄ョ Η0 00 1 'ι U9 "02- 919'91 £ 93 HOH 0 ΐΖ2ί 丄
0 £2*62 οο■ 'ι 90£*9 6i9'9l 98ε· 299 HOH 0 228丄 W1VI3H0 £ 2 * 62 οο ■ 'ι 90 £ * 9 6i9'9l 98ε299 HOH 0 228 丄 W1VI3H
0 89 ' 00 ' 'ι 00'22 988 Ι 98f "£9 199 HOH 0 mi 丄ョ Η0 89 '00' 'ι 00'22 988 Ι 98f "£ 9 199 HOH 0 mi 丄 Η
0 LQ' Z 00' 'ι 9L8"6 6εε·6ΐ- 122 '21 099 HOH 0 028 H1V13H0 LQ 'Z 00' 'ι 9L8 "6 6εε6ΐ- 122 '21 099 HOH 0 028 H1V13H
0 ' ε 00' ι 908 "81- o'i- 699 HOH 0 6L8Z W1V13H0 'ε 00' ι 908 "81- o'i- 699 HOH 0 6L8Z W1V13H
0 96*82 00' L l ' 02 I9i'frl- ^0 "91 899 HOH 0 8L8Z W1V13H0 96 * 82 00 'L l' 02 I9i'frl- ^ 0 "91 899 HOH 0 8L8Z W1V13H
0 1 ·9Ζ 00' Ί 6 '61 602 "El Ζ96"89 Ζ99 HOH 0 ZL81 W1V13H0 1 9 Ζ 00 'Ί 6 '61 602 "El Ζ96" 89 Ζ99 HOH 0 ZL81 W1V13H
0 00' 'ι 9tO'0l- i06'S£ 9£9"1- 999 HOH 0 9L8Z W1V13H0 00 '' ι 9tO'0l- i06'S £ 9 £ 9 "1- 999 HOH 0 9L8Z W1V13H
0 ε ' εε 00 ' L W21 ΠΟ^Ζ 898"9£ 999 HOH 0 9L8 W1V13H0 ε 'εε 00' L W21 ΠΟ ^ Ζ 898 "9 £ 999 HOH 0 9L8 W1V13H
0 οο■ L W61- S06'6 fr9 HOH 0 W1V13H0 οο ■ L W61- S06'6 fr9 HOH 0 W1V13H
0 00' L 896 "9 910ΌΙ- 186 '01 £99 HOH 0 £18Z W1V13H0 00 'L 896 "9 910ΌΙ- 186 '01 £ 99 HOH 0 £ 18Z W1V13H
0 96 "^ε 00' 1 9L671 οεο"89 2SS HOH 0 2L8 W1V13H0 96 "^ ε 00 '1 9L671 οεο" 89 2SS HOH 0 2L8 W1V13H
0 96*62 00' Ί lll'l LIVL- 6£0 £ 199 HOH 0 IL8Z W1V13H0 96 * 62 00 'Ί lll'l LIVL- 6 £ 0 £ 199 HOH 0 IL8Z W1V13H
0 0072 οο■ 1 698*91 οεο'ο- 099 HOH 0 018 W1V13H0 0072 οο ■ 1 698 * 91 οεο'ο- 099 HOH 0 018 W1V13H
0 9S '92 οο■ L £69*8 S01 '9Ζ- 10 ' ι- 6fS HOH 0 608Z W1V13H0 9S '92 οο ■ L £ 69 * 8 S01 '9Ζ- 10' ι- 6fS HOH 0 608Z W1V13H
0 Ζ6·82 00' Ί £Sf "0 982 ·ΖΙ 8 S HOH 0 8082 W1V13H0 Ζ6 · 82 00 'Ί £ Sf "0 982ΖΙ S 8 S HOH 0 8082 W1V13H
0 Ζ 'Π 00' L 92S HOH 0 腹 丄ョ Η 0 Ζ 'Π 00' L 92S HOH 0 belly Η
(0 ? )8拏 (0?) 8 Halla
681681
CZ.600/€OOZJf/X3d CZ.600 / € OOZJf / X3d
勵 OOZ O 0 89"l£ 00" I t^l '21 ZL9 H0H 0 Z1 L W丄 V丄ョ H 0 £8'l£ οο'ι 069 '02- 28Γ8- 119 HOH 0 82 H1V13H 0 65·8Ζ 00 ·1 92 61 89071- 261 ·8 019 HOH 0 01 L 隨丄ョ H 0 8 ' 9ε οο'ι 6£8Ί 096 ·8Ζ 609 HOH 0 698Z W1V13H 0 6 'οε 00 Ί 丄 19'01 - 86671 6L17"99 809 HOH 0 898丄 W1V13H 0 29 2 00 'I 891 '9- 191 ' ー 0 II Z09 HOH 0 Z99Z W丄 V丄ョ H 0 ΖΖ'Π 00 "L 6£ ·9 S69' - 98Z'6Z 909 HOH 0 998 HlViHH 0 εο· ε οο "L £ "21 016 '89 909 HOH 0 9982 v丄ョ H 0 £ '62 00 Ί 168 Ό ZL8'9 09S 'S HOH 0 98Z K1V13H 0 οζ'ΐε οο "ΐ S98.1L £98'££ Zf0"8 £09 HOH 0 £981 H1V13H 0 82. OS 00 Ί L89-91- 66£'U £61*91 209 HOH 0 298丄 丄ョ H 0 ZS"98 ΟΟ'Ι 968"0L U '9 £Ll "6fr 109 HOH 0 198丄 W1V13H 0 ΖΖ ΐ ΟΟΊ £80 Ό- m'zi- 009 HOH 0 098i IN1V13H 0 8f 2 00 Ί 09f '81 f9 Ί- £Z9'6 669 HOH 0 698i H1V13H 0 ε6·" 00 "L 9££"91 i90"2- 626 869 HOH 0 898i W1V13H 0 9ΖΌ£ ΟΟΊ 9 9- 092 I 6L6"9l Z6S HOH 0 1521 W1V13H 0 ΐε* 2 00 "L
Figure imgf000191_0001
02 '61 682.11 969 HOH 0 9981 W1V13H 0 00 "L 22Γ61- 809 908 "6S 969 HOH 0 998Z 1N1V13H 0 £6"Ζ2 ΟΟΊ 186"91- ZS6"0l L f6S HOH 0 L W1V13H 0
Figure imgf000191_0002
6£6"£- £69 HOH 0 £98i 1N1VI3H 0 29·εΖ 00 Ί Z61"0- Z69 HOH 0 2981 隨丄ョ H 0 06"L2 00 Ί 11 0 9L1OI 169 HOH 0 1981 W1V13H 0 9l"SZ 00 Ί 68 ' 9i9"£L- SZl - 069 HOH 0 0981 W1V13H 0 Ε6Ί2 00 Ί 90L'8 18 'ει— 282 '9- 689 HOH 0 6 W1V13H 0 8ε'92 00 Ί 009*8- 900'9L 8 '9 889 HOH 0 8f8i H1V13H 0 8S f 00 "I ιη·ι\ 9SZ'8fr Z8S HOH o mi W1V13H 0 2 OS 00 "L 69 2 Z08"fr£ 989 HOH o 9 W1V13H 0 90 "^ε 00 "L 906 ' 9S6'92 ΕΖΓ19 98S HOH o L W1V13H 0 8に 82 ΟΟΊ 666 Ό m L 806 ' HOH o i W1V13H 0 39*09 00 "I ZL9 926 "02 099 -6Z £89 HOH o %m W1V13H 0 6 εε οο ·ι 'z 0Z9"0£- 8 .6 289 HOH o z L W1V13H 0 ε εε οο·ι 9£9"C- 9ε 6 に 189 HOH o mL隱丄ョ H 0 ΐ8'εε οο Ί ,9l— Ζ9ΓΖ5 089 HOH o mi W1V13H Promote OOZ O 0 89 "l £ 00" I t ^ l '21 ZL9 H0H 0 Z1 LW 丄 V 丄 H 0 £ 8'l £ οο'ι 069 '02-28Γ8- 119 HOH 0 82 H1V13H 0 65 · 8Ζ 00 92 61 89071- 261 8 019 HOH 0 01 L Custom H 0 8 '9ε οο'ι 6 £ 8Ί 096 8Ζ 609 HOH 0 698Z W1V13H 0 6' οε 00 丄 19'01-86671 6L17 "99 809 HOH 0 898 丄 W1V13H 0 29 2 00 'I 891' 9- 191 'ー 0 II Z09 HOH 0 Z99Z W 丄 V 丄 H 0 ΖΖ'Π 00 "L 6 £ 9 S69'-98Z'6Z 909 HOH 0 998 HlViHH 0 εο · ε οο "L £" 21 016 '89 909 HOH 0 9982 v 丄 H 0 £ '62 00 168 168 Ό ZL8'9 09S 'S HOH 0 98Z K1V13H 0 οζ'ΐε οο "ΐ S98. 1L £ 98 '££ Zf0 "8 £ 09 HOH 0 £ 981 H1V13H 0 82.OS 00 Ί L89-91- 66 £' U £ 61 * 91 209 HOH 0 298 丄 H H 0 ZS" 98 ΟΟ'Ι 968 "0L U '9 £ Ll" 6fr 109 HOH 0 198 丄 W1V13H 0 ΖΖ ΐ 80 £ 80 Ό- m'zi- 009 HOH 0 098i IN1V13H 0 8f 2 00 Ί 09f '81 f9 Ί- £ Z9'6 669 HOH 0 698i H1V13H 0 ε6 "00" L 9 ££ "91 i90" 2- 626 869 HOH 0 898i W1V13H 0 9ΖΌ £ ΟΟΊ 9 9-092 I 6L6 "9l Z6S HOH 0 1521 W1V13H 0 ΐε * 2 00" L
Figure imgf000191_0001
02 '61 682.11 969 HOH 0 9981 W1V13H 0 00 "L 22Γ61- 809 908" 6S 969 HOH 0 998Z 1N1V13H 0 £ 6 "Ζ2 ΟΟΊ 186" 91-ZS6 "0l L f6S HOH 0 L W1V13H 0
Figure imgf000191_0002
6 £ 6 "£-£ 69 HOH 0 £ 98i 1N1VI3H 0 29 ・ εΖ 00 Ί Z61" 0- Z69 HOH 0 2981 Free H 0 06 "L2 00 Ί 11 0 9L1OI 169 HOH 0 1981 W1V13H 0 9l" SZ 00 Ί 68 '9i9 "£ L- SZl-069 HOH 0 0981 W1V13H 0 Ε6Ί2 00 Ί 90L'8 18' ει— 282 '9- 689 HOH 0 6 W1V13H 0 8ε'92 00 Ί 009 * 8- 900'9L 8' 9 889 HOH 0 8f8i H1V13H 0 8S f 00 "I ιη · ι 9SZ'8fr Z8S HOH o mi W1V13H 0 2 OS 00" L 69 2 Z08 "fr £ 989 HOH o 9 W1V13H 0 90" ^ ε 00 "L 906 '9S6'92 ΕΖΓ19 98S HOH o L W1V13H 08 to 82 ΟΟΊ 666 Ό m L 806' HOH oi W1V13H 0 39 * 09 00 "I ZL9 926" 02 099 -6Z £ 89 HOH o% m W1V13H 0 6 εε οο ι 'z 0Z9 "0 £-8.6 289 HOH oz L W1V13H 0 ε εεοοοι 9 £ 9” C- 9ε 6 to 189 HOH omL 丄 H H 0 ΐ8'εε οο Ί, 9l— Ζ9ΓΖ5 089 HOH o mi W1V13H
( 0)^)8拏 (0) ^) 8 Halla
0606
C.600/fOOZdf/X3d 19 表 8(その 42) C.600 / fOOZdf / X3d 19 Table 8 (Part 42)
HETATM 7873 0 HOH 613 50.200 -17.537 16.254 1.00 24.89 HETATM 7874 0 HOH 614 19.116 -5.382 20.187 1.00 28.55 HETATM 7875 0 HOH 615 11.023 13.925 2.295 1.00 29.32 HETATM 7876 0 HOH 616 -4.779 -9.190 15.657 1.00 27.45 HETATM 7877 0 HOH 617 9.195 13.747 7.232 1.00 31.62 HETATM 7878 0 HOH 618 48.629 19.263 20.227 1.00 34.19 HETATM 7879 0 HOH 619 16.537 -9.562 -9.738 1.00 37.60 HETATM 7880 0 HOH 620 51.957 6.491 4.879 1.00 28.33 HETATM 7881 0 HOH 621 7.221 -11.324 -14.116 1.00 25.55 HETATM 7882 0 HOH 622 50.404 1.412 -9.745 1.00 21.73 HETATM 7883 0 HOH 623 9.670 11.548 3.876 1.00 32.55 HETATM 7884 0 HOH 624 -10.772 19.243 2.488 1.00 26.56 HETATM 7885 0 HOH 625 6.462 19.502 17.191 1.00 30.76 HETATM 7886 0 HOH 626 46.621 15.613 -4.447 1.00 36.50 HETATM 7887 0 HOH 627 44.236 17.918 -3.582 1.00 28.25 HETATM 7888 0 HOH 628 5.758 3.626 -5.123 1.00 31.71 HETATM 7889 0 HOH 629 64.045 25.223 -6.154 1.00 32.14 HETATM 7890 0 HOH 630 46.656 4.609 -5.694 1.00 30.76 HETATM 7891 0 HOH 631 0.107 -9.096 -10.462 1.00 30.98 HETATM 7892 0 HOH 632 48.468 2.858 8.791 1.00 33.09 HETATM 7893 0 HOH 633 17.370 19.121 -15.145 1.00 29.16 HETATM 7894 0 HOH 634 24.294 17.833 -9.777 1.00 29.67 HETATM 7895 0 HOH 635 -6.432 3.475 13.585 1.00 29.34 HETATM 7896 0 HOH 636 68.341 -3.628 5.443 1.00 29.36 HETATM 7897 0 HOH 637 2.508 21.982 15.790 1.00 32.55 HETATM 7898 0 HOH 638 10.511 17.872 8.879 1.00 25.51 HETATM 7899 0 HOH 639 37.599 15.803 13.892 1.00 36.68 HETATM 7900 0 HOH 640 52.256 -3.030 -5.949 1.00 26.62 HETATM 7901 0 HOH 641 57.148 8.819 20.131 1.00 35.96 HETATM 7902 0 HOH 642 53.534 -0.940 18.859 1.00 27.91 HETATM 7903 0 HOH 643 12.101 1.622 7.682 1.00 35.09 HETATM 7904 0 HOH 644 -6.410 -9.586 10.728 1.00 31.60 HETATM 7905 0 HOH 645 46.664 1.292 4.009 1.00 22.08 92 表 8(その 43) HETATM 7873 0 HOH 613 50.200 -17.537 16.254 1.00 24.89 HETATM 7874 0 HOH 614 19.116 -5.382 20.187 1.00 28.55 HETATM 7875 0 HOH 615 11.023 13.925 2.295 1.00 29.32 HETATM 7876 0 HOH 616 -4.779 -9.190 15.657 1.00 27.45 HETATM 7.195 0 13.747 7.232 1.00 31.62 HETATM 7878 0 HOH 618 48.629 19.263 20.227 1.00 34.19 HETATM 7879 0 HOH 619 16.537 -9.562 -9.738 1.00 37.60 HETATM 7880 0 HOH 620 51.957 6.491 4.879 1.00 28.33 HETATM 7881 0 HOH 621 7.221 -11.324 -14. 0 HOH 622 50.404 1.412 -9.745 1.00 21.73 HETATM 7883 0 HOH 623 9.670 11.548 3.876 1.00 32.55 HETATM 7884 0 HOH 624 -10.772 19.243 2.488 1.00 26.56 HETATM 7885 0 HOH 625 6.462 19.502 17.191 1.00 30.76 HETATM 7886 0 HOH 626 46.1.00 15.613 36.50 HETATM 7887 0 HOH 627 44.236 17.918 -3.582 1.00 28.25 HETATM 7888 0 HOH 628 5.758 3.626 -5.123 1.00 31.71 HETATM 7889 0 HOH 629 64.045 25.223 -6.154 1.00 32.14 HETATM 7890 0 HOH 630 46.656 4.609 -5.694 1.00 30.76 HETA 0.107 -9.096 -10 .462 1.00 30.98 HETATM 7892 0 HOH 632 48.468 2.858 8.791 1.00 33.09 HETATM 7893 0 HOH 633 17.370 19.121 -15.145 1.00 29.16 HETATM 7894 0 HOH 634 24.294 17.833 -9.777 1.00 29.67 HETATM 7895 0 HOH 635 -6.432 3.475 13.585 1.00896 29.67 HOH 636 68.341 -3.628 5.443 1.00 29.36 HETATM 7897 0 HOH 637 2.508 21.982 15.790 1.00 32.55 HETATM 7898 0 HOH 638 10.511 17.872 8.879 1.00 25.51 HETATM 7899 0 HOH 639 37.599 15.803 13.892 1.00 36.68 HETATM 7900 0 HOH 640 52.256 -3.06 HETATM 7901 0 HOH 641 57.148 8.819 20.131 1.00 35.96 HETATM 7902 0 HOH 642 53.534 -0.940 18.859 1.00 27.91 HETATM 7903 0 HOH 643 12.101 1.622 7.682 1.00 35.09 HETATM 7904 0 HOH 644 -6.410 -9.586 10.728 1.00 31.60 HETATM 645 0664 4.009 1.00 22.08 92 Table 8 (Part 43)
HETATM 7906 0 HOH 646 8.474 0.560 22.223 1.00 32.75 0 HETATM 7907 0 HOH 647 30.181 22.639 -2.921 1.00 30.73 0 HETATM 7908 0 HOH 648 14.944 -25.472 -8.249 1.00 28.06 0 HETATM 7909 0 HOH 649 4.138 19.443 15.805 1.00 28.88 0 HETATM 7910 0 HOH 650 58.151 19.626 19.996 1.00 30.24 0 HETATM 7911 0 HOH 651 -8.027 12.568 2.037 1.00 31.78 0 HETATM 7912 0 HOH 652 47.605 20.314 15.928 1.00 26.33 0 HETATM 7913 0 HOH 653 24.943 -9.574 1.929 1.00 32.29 0 HETATM 7914 0 HOH 654 28.496 -5.394 -1.546 1.00 34.85 0 HETATM 7915 0 HOH 655 50.560 11.846 18.940 1.00 34.59 0 HETATM 7916 0 HOH 656 66.245 27.475 -1.291 1.00 29.70 0 HETATM 7917 0 HOH 657 48.100 4.145 4.909 1.00 42.36 0 HETATM 7918 0 HOH 658 29.685 26.764 -11.981 1.00 29.45 0 HETATM 7919 0 HOH 659 59.417 -18.937 17.062 1.00 33.68 0 HETATM 7920 0 HOH 660 - 8.146 0.721 -5.728 1.00 35.17 0 HETATM 7921 0 HOH 661 -10.941 -8.318 9.887 1.00 33.06 0 HETATM 7922 0 HOH 662 -2.680 4.163 6.216 1.00 32.78 0 HETATM 7923 0 HOH 663 51.975 -15.260 -2.959 1.00 26.36 0 HETATM 7924 0 HOH 664 12.061 36.903 ' 5.957 1.00 34.51 0 HETATM 7925 0 HOH 665 -4.557 -19.423 18.660 1.00 35.40 0 HETATM 7926 0 HOH 666 11.250 8.307 -6.479 1.00 34.17 0 HETATM 7927 0 HOH 667 5.524 2.668 26.006 1.00 35.21 0 HETATM 7928 0 HOH 668 -1.021 21.160 -19.404 1.00 30.52 0 HETATM 7929 0 HOH 669 -3.858 -3.925 3.385 1.00 37.80 0 HETATM 7930 0 HOH 670 8.551 5.034 24.458 1.00 41.64 0 HETATM 7931 0 HOH 671 61.073 4.956 16.185 1.00 35.81 0 HETATM 7932 0 HOH 672 17.736 10.354 -4.719 1.00 37.34 0 HETATM 7933 0 HOH 673 40.852 15.359 7.774 1.00 33.58 0 HETATM 7934 0 HOH 674 46.996 13.160 16.438 1.00 31.11 0 HETATM 7935 0 HOH 675 52.826 -21.644 -3.822 1.00 31.73 0 HETATM 7936 0 HOH 676 18.362 33.782 9.730 1.00 28.55 0 HETATM 7937 0 HOH 677 63.461 -10.742 17.403 1.00 35.52 0 HETATM 7938 0 HOH 678 25.308 -7.766 4.637 1.00 27.03 0 0 00•I 969 "9- 669 '9- HZ HOH 0 I16i W1V13HHETATM 7906 0 HOH 646 8.474 0.560 22.223 1.00 32.75 0 HETATM 7907 0 HOH 647 30.181 22.639 -2.921 1.00 30.73 0 HETATM 7908 0 HOH 648 14.944 -25.472 -8.249 1.00 28.06 0 HETATM 7909 0 HOH 649 4.138 19.443 15.805 1.00 28.88 0 HETA HOH 650 58.151 19.626 19.996 1.00 30.24 0 HETATM 7911 0 HOH 651 -8.027 12.568 2.037 1.00 31.78 0 HETATM 7912 0 HOH 652 47.605 20.314 15.928 1.00 26.33 0 HETATM 7913 0 HOH 653 24.943 -9.574 1.929 1.00 32.29 0 HETATM 7914 0OH 5.394 -1.546 1.00 34.85 0 HETATM 7915 0 HOH 655 50.560 11.846 18.940 1.00 34.59 0 HETATM 7916 0 HOH 656 66.245 27.475 -1.291 1.00 29.70 0 HETATM 7917 0 HOH 657 48.100 4.145 4.909 1.00 42.36 0 HETATM 7918 0 HOH 658 29.685 26.7 29.45 0 HETATM 7919 0 HOH 659 59.417 -18.937 17.062 1.00 33.68 0 HETATM 7920 0 HOH 660-8.146 0.721 -5.728 1.00 35.17 0 HETATM 7921 0 HOH 661 -10.941 -8.318 9.887 1.00 33.06 0 HETATM 7922 0 HOH 662 -2.680 4.163 6.216 32.78 0 HETATM 7923 0 HOH 663 51.975 -15.260 -2.959 1.00 26.36 0 HETATM 7924 0 HOH 664 12.061 36.903 '5.957 1.00 34.51 0 HETATM 7925 0 HOH 665 -4.557 -19.423 18.660 1.00 35.40 0 HETATM 7926 0 HOH 666 11.250 8.307 -6.479 1.00 34.17 0 HETATM 7927 0 HOH 667 5.524 2.668 26.006 1.00 35.21 0 HETATM 7927 0 HOH 667 5.524 2.668 26.006 1.00 35.21 0 7928 0 HOH 668 -1.021 21.160 -19.404 1.00 30.52 0 HETATM 7929 0 HOH 669 -3.858 -3.925 3.385 1.00 37.80 0 HETATM 7930 0 HOH 670 8.551 5.034 24.458 1.00 41.64 0 HETATM 7931 0 HOH 671 61.073 4.956 16.185 1.00 35.81 0 HETA HOH 672 17.736 10.354 -4.719 1.00 37.34 0 HETATM 7933 0 HOH 673 40.852 15.359 7.774 1.00 33.58 0 HETATM 7934 0 HOH 674 46.996 13.160 16.438 1.00 31.11 0 HETATM 7935 0 HOH 675 52.826 -21.644 -3.822 1.00 31.73 0 HETATM 7936 0OH 33.782 9.730 1.00 28.55 0 HETATM 7937 0 HOH 677 63.461 -10.742 17.403 1.00 35.52 0 HETATM 7938 0 HOH 678 25.308 -7.766 4.637 1.00 27.03 0 0 00 • I 969 "9- 669 '9- HZ HOH 0 I16i W1V13H
0 ' 00 9l8'£l - ζοε·" - 562·0 OU HOH O 0Z6 l/UV丄ョ H0 '00 9l8' £ l-ζοε · ”-562 · 0 OU HOH O 0Z6 l / UV
0 に^ 00 •I I08'2l 60 HOH O 696 W丄 V丄ョ H0 to ^ 00 • I I08'2l 60 HOH O 696 W 丄 V 丄 H
0 00 •I S£0"9 129 '8 90Z HOH 0 896丄 W1V13H0 00 • I S £ 0 "9 129 '8 90Z HOH 0 896 丄 W1V13H
0 00 Ί £89'6l- '[ Z£6'09 LQL HOH 0 Z96 W1V13H0 00 Ί £ 89'6l- '[Z £ 6'09 LQL HOH 0 Z96 W1V13H
0 09"2£ 00 ■I Z 8'9 Z69"9- 90丄 HOH 0 9961 W1V13H0 09 "2 £ 00 ■ I Z 8'9 Z69" 9- 90 丄 HOH 0 9961 W1V13H
0 S 00 n £90 "6- 902 HOH 0 S962 W1V13H0 S 00 n £ 90 "6- 902 HOH 0 S962 W1V13H
0 OS '82 00 "L £88'£L 896 Ί2 286 '9 OL HOH 0 ^961 W1V13H0 OS '82 00 "L £ 88 '£ L 896 Ί2 286' 9 OL HOH 0 ^ 961 W1V13H
0 69·9£ 00 "L "9- 9U'0 εο丄 HOH O i%L IN1V13H0 699 £ 00 "L" 9-9U'0 εο 丄 HOH O i% L IN1V13H
0 16 '82 00 ■I 19£7- 8SI Ί- Z02 HOH 0 Z L WIV13H0 16 '82 00 I 19 £ 7-8SI Ί- Z02 HOH 0 Z L WIV13H
0 9Γ6Ε 00 •I 09671- ΟΖ^Ή 102 HOH 0 1%L 丄 V丄ョ H0 9Γ6Ε 00 • I 09671- ΟΖ ^ Ή 102 HOH 0 1% L 丄 V 丄 H
0 00 'I 299 "9 899 ΌΙ OO HOH O 0961 W1V13H0 00 'I 299 "9 899 ΌΙ OO HOH O 0961 W1V13H
0 οι ε 00 ■I S68O ト 669 HOH O 6962 W1V13H0 οι ε 00 ■ I S68O G 669 HOH O 6962 W1V13H
0 L6'9£ 00 •I Wト 091*81- 869 HOH 0 8S6i 丄ョ H0 L6'9 £ 00I W 091 * 81-869 HOH 0 8S6i
0 00 •I m'z 829 £- 699 "il i69 HOH O 2961 H1V1HH0 00 • I m'z 829 £-699 "il i69 HOH O 2961 H1V1HH
0 ιε·9ε 00 ,1 S91 "SI 889 ε ·8- 969 HOH O 9S6 W1V13H0 ιε9ε 00, 1 S91 "SI 889 ε8-969 HOH O 9S6 W1V13H
0 ΙΓ82 00 Ί ε ει £26·ε9 969 HOH 0 S96i W1V13H0 ΙΓ82 00 Ίε ει £ 26 ・ ε9 969 HOH 0 S96i W1V13H
0 2 '62 00 •I £9S'Z 6Z6'S9 69 HOH 0 L W1V13H0 2 '62 00I £ 9S'Z 6Z6'S9 69 HOH 0 L W1V13H
0 99'62 00 "l Z68 L ε·ΐ9 £69 HOH O W1VI3H0 99'62 00 "l Z68 L εΐ9 £ 69 HOH O W1VI3H
0 OO'lfr 00 •i 0LS - ^9 369 HOH 0 296i W1V13H0 OO'lfr 00 • i 0LS-^ 9 369 HOH 0 296i W1V13H
0 9978 00 •I Sl6'6l S6S L69 HOH 0 1962 W丄 V丄ョ H0 9978 00I Sl6'6l S6S L69 HOH 0 1962 W 丄 V 丄 H
0 S6"0£ 00 ■I 069 HOH 0 0S6Z W1V13H0 S6 "0 £ 00 ■ I 069 HOH 0 0S6Z W1V13H
0 6Z'2£ 00 Ί 29 61- 0L9"69 689 HOH 0 6 6 W1V13H0 6Z'2 £ 00 Ί 29 61-0L9 "69 689 HOH 0 6 6 W1V13H
0 6£·62 00 ,1 19Γ8 L9L S69'8- 889 HOH 0 8 62 VUV丄ョ H0 6 £ 62 00, 1 19Γ8 L9L S69'8- 889 HOH 0 8 62 VUV
0 9丄 'ιε 00 ,1 922 '9 Z89 HOH 0 LHL H1V13H0 9 丄 'ιε 00, 1 922' 9 Z89 HOH 0 LHL H1V13H
0 00 ■i 9 ^ l - 8οε·9ε 969 L- 989 HOH 0 mL W1V13H0 00 i 9 ^ l-8οε 9ε 969 L- 989 HOH 0 mL W1V13H
0 96 '62 00 ,1 1 5 'Ρ- οεε'ι 196*09 S89 HOH 0 mi W丄 V丄ョ H0 96 '62 00, 1 1 5 'Ρ- οεε'ι 196 * 09 S89 HOH 0 mi W 丄 V 丄 H
0 zz 00 'I 6 '£ 996*01- 89 HOH 0 mL W1V13H0 zz 00 'I 6' £ 996 * 01-89 HOH 0 mL W1V13H
0 90· ε 00 •I 9£9"9 £89 HOH 0 mL W1V13H0 90 · ε 00 • I 9 £ 9 "9 £ 89 HOH 0 mL W1V13H
0 9ε·2ε 00 ,1 SM'9 L i '62 289 HOH 0 ZHL W1V13H0 9ε2ε 00, 1 SM'9 L i '62 289 HOH 0 ZHL W1V13H
0 69'9C 00' Ί 8L2'8L- L89 HOH 0 W1V13H0 69'9C 00 'Ί 8L2'8L- L89 HOH 0 W1V13H
0 90·9£ 00 Ί 169'Sl 089 HOH 0 mL W1V13H0 90 9 £ 00 169 169'Sl 089 HOH 0 mL W1V13H
0 '8£ 00' ■I 926^- 990"6l 182 '62 6Z9 HOH 0 N1V13H 0 '8 £ 00' ■ I 926 ^-990 "6l 182 '62 6Z9 HOH 0 N1V13H
( 0) ）8拏 (0)) 8 Halla
ε 6 τ ε 6 τ
ez.60o/eoozdf/x3d 0 L0'89 00 *L 80971- OLZ"OZ- WO - m HOH 0 t^008 H1V13H 0 LL'U 00 'I 298^2- Wfr 0 8 Z L HOH 0 £008 W1V丄ョ Η 0 86· l 00· I S69OL- LOL ' 6 ' Z L HOH 0 2008 W1V13H 0 81 'S£ 00.1 6 l "91- 169 · 628'£l- I L HOH 0 1008 W1V13H 0 £6"8£ 00" I OS 71 9917 £H Ί9 0 Z HOH 0 0009 W1V13H 0 12'Π 00"ί Mに^- 6 S ' Ζ 6£Z HOH 0 6662 W1V13H 0 6Ζ·82 00 'L 919 '9- 9L6'8l £19'92 2L HOH 0 8662 隨丄ョ Η 0 ZO'PZ 00 'L m-\z 288 '8 9^8* LZL HOH 0 1662 H1V13H 0 ' oo'i 6 ΙΖ6"8 9"9 9£I HOH 0 966 W1V13H 0 S"oe oo'i 319 ·ει WS£ 6 9EZ HOH 0 966i W1V13H 0 6に 9£ OO'I Z08"Sl- OOS'Ol- 0£1 '9 L HOH 0 t^662 W1V13H 0 98 '8Z OO'I 6S0'Z- 960 "8t^ £EZ HOH 0 E662 W1V13H 0 ε'6ε oo Ί 20 '9- εεに u 126 '69 ZIL HOH 0 2661 H1V13H 0 00 £ OO'I 919 '2 2Z8'9 IS丄 HOH 0 166 W1V13H 0 96 "92 00" I Il6'£ Zf6"9l ilO'OL- O HOH 0 066Z H1V13H 0 OZ'SZ OO'I 6丄 6·ε 266 Ό tO6'0L 62丄 HOH 0 686 IUV丄ョ Η 0 'n oo Ί 286·1- 866 ΊΙ- 98Γ9- Ul HOH 0 886丄 H1V13H 0 6 ' 12 00 εεο'8- Z9S-Z- 9C2"9l Z2Z HOH 0 mi W1V13H 0 Ifr'l OO'I 'Li 92Z HOH 0 986 W1V13H 0 98'0fr OO'I 8 9·ε - 0に οε 926^9 921 HOH 0 S86i W1V13H 0 80· 00 Ί £90*02- 299'£l L ^- HOH 0 L W1V13H 0 li'ZP OO'I 2927L- £96"9£ 0Z9"E9 IZL HOH 0 £862 W1V13H 0 ΡΡΉ OO'I 990*0^ IU HOH 0 286 W1V13H 0 ^"8G OO'I 220·91- 2S0'f 9S6 "6 122 HOH 0 1862 W1V13H 0 ε " oo'i 06f ' - Z90"S2 £8971 OZZ HOH 0 0862 W1V13H 0 ε 'εε ΟΟΊ 198'OL- W - 96Π 6U HOH 0 6i6i HiVi3H 0 ΙΓ82 00 Ί L2ViZ 619"8 188^9 81Z HOH 0 L5L H1V13H 0 997S OO'I 9£8'S- 888 ^1 69i'8fr LZ HOH 0 6Z H1V13H 0 6 OO'I Z£6 L- 912 HOH 0 9丄 6 H1V13H 0 9ε"ζε OO'I 026' ES67 0 S- SIZ HOH 0 SZ6 W1V13H 0 117£ OO'L UL ' 896'6- Z HOH 0 W1V13H 0 66'8£ OO'L 99-L7 ZLfl- 9E6.92 l\l HOH 0 S16i W1V13H 0 21"0t7 OO'L Z22*6l 98 1 2 HOH 0 ZL^L H1V13H ez.60o / eoozdf / x3d 0 L0'89 00 * L 80971-OLZ "OZ-WO-m HOH 0 t ^ 008 H1V13H 0 LL'U 00 'I 298 ^ 2- Wfr 0 8 ZL HOH 0 £ 008 W1V 丄 0 86 l00 · I S69OL- LOL '6' ZL HOH 0 2008 W1V13H 0 81 'S £ 00.1 6 l "91-169 Ί9 0 Z HOH 0 0009 W1V13H 0 12'Π 00 "ί M ^-6 S 'Ζ 6 £ Z HOH 0 6662 W1V13H 0 6Ζ82 00' L 919 '9-9L6'8l £ 19'92 2L HOH 0 8662 Η0 ZO'PZ 00 'L m- \ z 288' 8 9 ^ 8 * LZL HOH 0 1662 H1V13H 0 'oo'i 6 ΙΖ6 "8 9" 9 9 £ I HOH 0 966 W1V13H 0 S " oe oo'i 319εε WS £ 6 9EZ HOH 0 966i W1V13H 06 to 9 £ OO'I Z08 "Sl- OOS'Ol- 0 £ 1 '9 L HOH 0 t ^ 662 W1V13H 0 98' 8Z OO'I 6S0'Z- 960 "8t ^ £ EZ HOH 0 E662 W1V13H 0 ε'6ε oo Ί 20 '9- εε u 126 '69 ZIL HOH 0 2661 H1V13H 0 00 £ OO'I 919' 2 2Z8'9 IS 丄 HOH 0 166 W1V13H 0 96 "92 00" I Il6 '£ Zf6 "9l ilO'OL- O HOH 0 066Z H1V13H 0 OZ'SZ OO'I 6 丄 6ε266 Ό tO6'0L 62 丄 HOH 0 686 IUV Η 0 'n oo Ί 286 · 1-866 ΊΙ- 98Γ9- Ul HOH 0 886 丄 H1V13H 0 6 '12 00 εεο'8- Z9S-Z- 9C2 "9l Z2Z HOH 0 mi W1V13H 0 Ifr'l OO'I 'Li 92Z HOH 0 986 W1V13H 0 98'0fr OO'I 8 9ε-0 to οε 926 ^ 9 921 HOH 0 S86i W1V13H 0 8000 00 Ί £ 90 * 02 -299 '£ l L ^-HOH 0 L W1V13H 0 li'ZP OO'I 2927L- £ 96 "9 £ 0Z9" E9 IZL HOH 0 £ 862 W1V13H 0 ΡΡΉ OO'I 990 * 0 ^ IU HOH 0 286 W1V13H 0 ^ "8G OO'I 22091-2S0'f 9S6" 6 122 HOH 0 1862 W1V13H 0 ε "oo'i 06f '-Z90" S2 £ 8971 OZZ HOH 0 0862 W1V13H 0 ε' εε 198 198'OL-W -96Π 6U HOH 0 6i6i HiVi3H 0 ΙΓ82 00 Ί L2ViZ 619 "8 188 ^ 9 81Z HOH 0 L5L H1V13H 0 997S OO'I 9 £ 8'S- 888 ^ 1 69i'8fr LZ HOH 0 6Z H1V13H 0 6 OO'I Z £ 6 L- 912 HOH 0 9 丄 6 H1V13H 0 9ε''ζε OO'I 026 'ES67 0 S- SIZ HOH 0 SZ6 W1V13H 0 117 £ OO'L UL'896'6-Z HOH 0 W1V13H 0 66'8 £ OO 'L 99-L7 ZLfl-9E6.92 l \ l HOH 0 S16i W1V13H 0 21 "0t7 OO'L Z22 * 6l 98 1 2 HOH 0 ZL ^ L H1V13H
(9170)^)8拏 6 I(9170) ^) 8 Halla 6 I
f.600/COOidf/X3d f.600 / COOidf / X3d
I'ZCflO/^OOZ: OAV
Figure imgf000196_0001
I'ZCflO / ^ OOZ: OAV
Figure imgf000196_0001
υ υυ n  υ υυ n
Ubb c- 8Z8 i ~  Ubb c-8Z8 i ~
to 60 6b HUH 0  to 60 6b HUH 0
υ υυ ο6¾ l L- 669 L 99 L i- HOH 0 SE08 W丄 V丄: 1H υ υυ ο6¾ l L- 669 L 99 L i- HOH 0 SE08 W 丄 V 丄: 1H
0 So v 00 L 0 91 896 'LI E L6 "9£ vLL HOH 0 0 So v 00 L 0 91 896 'LI E L6 "9 £ vLL HOH 0
0 it 62 00 L 097 SI Z99 '91- ILL HOH 0 £E08 IN丄 Vi3H 0 it 62 00 L 097 SI Z99 '91-ILL HOH 0 £ E08 IN 丄 Vi3H
0 60 'ΐε 00 ■ L S3 0- Z L 'IZ 298 "9£ ILL HOH 0 £ 08 W丄 V丄 3Η0 60 'ΐε 00 ■ L S3 0- Z L' IZ 298 "9 £ ILL HOH 0 £ 08 W 丄 V 丄 3Η
0 66 "9£ 00 Ί 290 '9 - £11 '21 - 2 Z ILL HOH 0 ΙΕ09 WiV丄 3Η0 66 "9 £ 00 Ί 290 '9-£ 11 '21-2 ZILL HOH 0 ΙΕ09 WiV 丄 3Η
0 εε "εε 00 ' ι 060 Ή - 9S0 '8 - QLL HOH 0 0BO8 W丄 V丄 3H0 εε "εε 00 'ι 060 Ή-9S0' 8-QLL HOH 0 0BO8 W 丄 V 丄 3H
0 96 'SE 00 999 "ε 0 ' 12 - Z0Z · i 69 HOH 0 6208 丄 V丄 3H0 96 'SE 00 999 "ε 0' 12-Z0Zi 69 HOH 0 6208 丄 V 丄 3H
0 16 'Ζ 00 ' ι £20 '9- 99Z 72- I ' ^ 89丄 HOH 0 8208 W1V丄 3H0 16 'Ζ 00' ι £ 20 '9- 99Z 72- I' ^ 89 丄 HOH 0 8208 W1V 丄 3H
0 28 'OS 00 ' ι '62 08 '£9 Z9i HOH 0 208 IN上 V丄 3H0 28 'OS 00' ι '62 08 '£ 9 Z9i HOH 0 208 IN V 丄 3H
0 61 '8ε 00 ' ' ι L99 'LI 80L *2£ t^S6 '9 991 HOH 0 9208 11LVI3H0 61 '8ε 00' 'ι L99' LI 80L * 2 £ t ^ S6 '9 991 HOH 0 9208 11LVI3H
0 '9£ 00 Ί 168 "12 196 '8L- 06 991 HOH 0 9208 l/ V丄 3H0 '9 £ 00 Ί 168 "12 196' 8L- 06 991 HOH 0 9208 l / V 丄 3H
0 £9 '62 00 Ί 631 '21 - 192 * L - 280 "0t? 92 HOH 0 0 £ 9 '62 00 Ί 631 '21-192 * L-280 "0t? 92 HOH 0
0 18 *ζε 00 ' Ί 217 "L2 610 "l I 206 OS £91 HOH 0 £208 IN丄 V丄 3H 0 18 * ζε 00 'Ί 217 "L2 610" l I 206 OS £ 91 HOH 0 £ 208 IN 丄 V 丄 3H
0 6 '2£ 00 ' ι 162 ΊΙ 666 *9l 992 "6 29Z HOH 0 2208 1N1V丄 3H0 6 '2 £ 00' ι 162 ΊΙ 666 * 9l 992 "6 29Z HOH 0 2208 1N1V 丄 3H
0 £8 "8S 00' Ί 88S "01- LE0'82 I9i HOH 0 1208 IN丄 V丄 3H0 £ 8 "8S 00 'Ί 88S" 01- LE0'82 I9i HOH 0 1208 IN 丄 V 丄 3H
0 19 '62 00 ' ■ L £29 *8- SLO'IZ- 091 HOH 0 0208 IN丄 V丄 3H0 19 '62 00 '■ L £ 29 * 8- SLO'IZ- 091 HOH 0 0208 IN 丄 V 丄 3H
0 82 '82 00 ' Ί Lt?9 *£L- 696 "L- III "09 69ί HOH 0 6108 li Vl3H 0 82 '82 00 'Ί Lt? 9 * £ L-696 "L-III" 09 69ί HOH 0 6108 li Vl3H
1  1
0 ΙΖ "82 00 ' ■ L 811 '01 - ill 11- 002 '92 892 HOH 0 8108 1N1VI3H 0 ΙΖ "82 00 '■ L 811 '01-ill 11- 002 '92 892 HOH 0 8108 1N1VI3H
0 62 "8£ 00 ' L 080 LI S£ " t? HOH 0 LOS IN丄 V丄 3H0 62 "8 £ 00 'L 080 LI S £" t? HOH 0 LOS IN 丄 V 丄 3H
0 91 2£ 00 L S 9 ε- . SSZ 9t 106 '91 9Si HOH 0 9108 WiV丄 3H
Figure imgf000196_0002
L Lvv Ζ tffc I- HOH 0 S luo Wl w u0 91 2 £ 00 LS 9 ε-. SSZ 9t 106 '91 9Si HOH 0 9108 WiV 丄 3H
Figure imgf000196_0002
L Lvv Ζ tffc I- HOH 0 S luo Wl wu
V丄： IH
Figure imgf000196_0003
c c 1 L nUoo ui丄 1 w V丄 1 "：3 iuH υ Π 'CO υυ ' 1 V 丄: IH
Figure imgf000196_0003
cc 1 L nUoo ui 丄 1 w V 丄 1 ": 3 iuH υ CO 'CO υυ' 1
L ooU y L C / u HnUu n L ooU y L C / u HnUu n
H 6 lUo 丄 V丄： JH H 6 lUo 丄 V 丄: JH
0 ' 0 00' "L 29 - 6i9 '6- 19Z HOH 0 1108 H1V13H0 '0 00' "L 29-6i9 '6- 19Z HOH 0 1108 H1V13H
0 OS '82 00' 1 W6 0S2 HOH 0 0108 W1V13H0 OS '82 00 '1 W6 0S2 HOH 0 0108 W1V13H
0 S S£ 00' Ί 609 Ό9 617丄 HOH 0 6008 W1V13H0 S S £ 00 'Ί 609 Ό9 617 丄 HOH 0 6008 W1V13H
0 ·9£ 00' ■1 £06 "0 Z19"6- 8 HOH 0 8008 W1V13H0 · 9 £ 00 '■ 1 £ 06 "0 Z19" 6-8 HOH 0 8008 W1V13H
0 00' Ί 6Ζ6ΌΙ 091 ·0Ζ nv%\ HOH 0 008 W1V13H0 00 'Ί 6Ζ6ΌΙ 091 0Ζ nv% \ HOH 0 008 W1V13H
0 6ε·ζε 00' Ί 6 8 · I- 821 ' ー WO- 9PL HOH 0 9008 W1V13H0 6εζζ00 'Ί 6 8I-821' ー WO-9PL HOH 0 9008 W1V13H
0 9 2ε 00' Ί 9Z6 1- 916Ί2 09ΕΌ9 HOH 0 S008 丄ョ H 0 9 2ε 00 'Ί 9Z6 1- 916Ί2 09ΕΌ9 HOH 0 S008
(9 0) ）8拏 (9 0)) 8 Halla
96 C.600/COOZdf/X3d 1 " ΠΟ請 Z OAV 68 'Π 00 Ί 69 - 199Ό2- •L- 018 H0H 0 0Z08 H1V13H96 C.600 / COOZdf / X3d 1 "Contract Z OAV 68 'Π 00 Ί 69-199Ό2-L-018 H0H 0 0Z08 H1V13H
08 Ε 00 Ί S68"S- 6οε ·ο- S2£ •01 608 HOH 0 6908 W1V13H s ·οε 00 •ι ZZ2'9l ·0 808 H0H 0 oyuo Irt ΐ "^ε 00 .1 0 0 ^1 991 •09 208 HOH 0 IV JH ε'6ε 00 •ι 6 ·0 £8'S2 - 16Z ■02 908 HOH 0 08 Ε 00 Ί S68 "S-6οε · ο- S2 £ • 01 608 HOH 0 6908 W1V13H s · οε 00 • ι ZZ2'9l 09 208 HOH 0 IV JH ε'6ε 00 • ι 6 £ 8'S2-16Z02 908 HOH 0
00 Ί 620 "9- εζε ·81 f98 •01 - 908 HOH 0 aUS  00 Ί 620 "9- εζε81 f98 • 01-908 HOH 0 aUS
9ε·εε 00 ■ι 99-6- 29 ■ i f08 HOH 0 no IV εε'9 00 Ί 080 'ε - 1957- 2£0 ■1 £08 HOH 0 t9Uo j 9ε ・ εε 00 ■ ι 99-6- 29 ■ i f08 HOH 0 no IV εε'9 00 Ί 080 'ε-1957- 2 £ 0 ■ 1 £ 08 HOH 0 t9Uo j
90·εε 00 'ι l£6 ' - 28£·£1 Z08 HOH 0 90εε 00 'ι l £ 6'-28 ££ 1 Z08 HOH 0
86'ιε 00' 'ι 8S0 'LI 169-9 210 OL 108 HOH 0 ill コ 86'ιε 00 '' ι 8S0 'LI 169-9 210 OL 108 HOH 0 ill
ΖΟ'Ζΐ 00 Ί I i '0 - 1 ' 02- ε *69 009 HOH 0 ΖΟ'Ζΐ 00 Ί I i '0-1' 02- ε * 69 009 HOH 0
00 ■ι 919 'Ζ- 19£"Z2 661 HOH 0 bbUo ill コ 'εε 00 Ί 9£9 'LI 6·2 0 6 '89 86Z HOH 0 oc no W V JH 00 ■ ι 919 'Ζ-19 £ "Z2 661 HOH 0 bbUo ill' 'εε 00 Ί 9 £ 9' LI 6.22 6 '89 86Z HOH 0 oc no W V JH
19·8ε 00' ■ι 026'8L 966 ' 9 IU HOH 0 コ 19 · 8ε 00 '■ ι 026'8L 966' 9 IU HOH 0
til コ u til co u
00 'ι S "Z- 619*21- ΌΖΐ ■9£ 96 HOH 0 ftp 00 'ι S "Z- 619 * 21- ΌΖΐ ■ 9 £ 96 HOH 0 ftp
96 '62 00' Ί 8ζε "ε ^9971- •£ 96i HOH 0 c no W V dH 96 '62 00 'Ί 8ζε "ε ^ 9971- • £ 96i HOH 0 c no W V dH
00' Ί FD I 6 186 Ό 8εε '91 HOH 0 W V iH ·εε 00' Ί ' L L- nz-Q 8L6 ■I- £6i HOH 0 ccno コ u οε 00' Ί of L L •61 Z6i HOH 0 cno u00 'Ί FD I 6 186 Ό 8εε '91 HOH 0 WV iH ・ εε 00' Ί 'L L- nz-Q 8L6 I- £ 6i HOH 0 ccno u
8972 00' Ί 16£ "81- 920 '^ε L6丄 HOH 0 L H V JH η~π οο■ Ί 9il ·61- 811 ΊΙ 06i HOH 0 Ιίϊ V l8972 00 'Ί 16 £ "81- 920' ^ ε L6 丄 HOH 0 L H V JH η ~ π οο ■ Ί 9il61- 811 ΊΙ 06i HOH 0 Ιίϊ V l
2S' οο■ Ί 910*61 082 •8 681 HOH 0 yuv丄ョ H2S 'οο ■ Ί 910 * 61 082 • 8 681 HOH 0 yuv 丄
18·62 00' Ί 2£2"9- ^96 "9- 80 1 881 HOH 0 8 08 W1V13H1862 00 'Ί 2 £ 2 "9- ^ 96" 9- 80 1 881 HOH 0 8 08 W1V13H
8272 00' Ί ΙΙΓ0- LOL '9 - HOH 0 Lm H1V13H8272 00 'ΙΙΓ ΙΙΓ0- LOL' 9-HOH 0 Lm H1V13H
92'9£ 00' 1 108 '02 98i HOH 0 9 H1V13H92'9 £ 00 '1 108 '02 98i HOH 0 9 H1V13H
00 00' '8ΐ 020 •£L 98 HOH 0 9f08 W丄 V丄ョ H00 00 '' 8ΐ 020 • £ L 98 HOH 0 9f08 W 丄 V 丄 H
09·81 00' 'ι 2 2 "0 I i ■ε 82 HOH .0 W1V13H ΐ8·ιε 00' 1 に - Z9879 £8i HOH 0 08 H1V13H09.81 00 '' ι 2 2 "0 I i ■ ε 82 HOH .0 W1V13H ΐ8 · ιε 00 '1-Z9879 £ 8i HOH 0 08 H1V13H
99'82 00' L 8 £L - l7£ 281 HOH 0 08 H1V13H99'82 00 'L 8 £ L-l7 £ 281 HOH 0 08 H1V13H
00' Ί OOS'S- 6" ·ε ZQl •8 18i. HOH 0 08 W1V13H00 'Ί OOS'S-6 "· ε ZQl • 8 18i. HOH 0 08 W1V13H
29'9£ 00' Ί 8887- 0丄 I ■ιε 08 HOH 0 0 08 WiVlBH29'9 £ 00 'Ί 8887-0 丄 I ■ ιε 08 HOH 0 0 08 WiVlBH
96 £ οο■ Ί - 129^2 SZ6 •29 6 Z HOH 0 6£08 H1V13H ζι ·εε 00' '1 ιεζ*6ΐ- ε6 ε 69 •9一 822 HOH 0 8£08 W1V13H 96 £ οο ■ Ί-129 ^ 2 SZ6 • 29 6 Z HOH 0 6 £ 08 H1V13H ζι · εε 00 '' 1 ιεζ * 6ΐ- ε6 ε 69
96 lO/WOZ OAV 0 ε "ο 00 ι L9 V ZLV 9 S18"9- HOH 0 £018 W丄 V13H96 lO / WOZ OAV 0 ε "ο 00 ι L9 V ZLV 9 S18" 9- HOH 0 £ 018 W 丄 V13H
0 09 "9 00 ' ι 917 9 6 6 '0£- 906 "09 HOH 0 6UL8 1N1V丄 3H0 09 "9 00 'ι 917 9 6 6' 0 £-906" 09 HOH 0 6UL8 1N1V 丄 3H
0 86 '62 00 • ι 9ε 'ζζ 999 '8 6t^9 •IS HOH 0 L0L8 IN丄 V丄 3H0 86 '62 00 • ι 9ε 'ζζ 999' 8 6t ^ 9IS HOH 0 L0L8 IN 丄 V 丄 3H
0 Si ·0 00 •ι 96L '91 9 S 'L 9£0 ■6 0^8 HOH 0 0018 丄 3H0 Si · 00 00 • ι 96L '91 9 S 'L 9 £ 0 ■ 6 0 ^ 8 HOH 0 0018 丄 3H
0 00 •ι 990 *ει- 699 l - £26飞 6£8 HOH 0 6608 WIV丄 3H0 00 • ι 990 * ει- 699 l-£ 26 飞 6 £ 8 HOH 0 6608 WIV 丄 3H
0 6 ·6ε 00 Ί SS0 ·9 £Z6 ΌΙ 686 ·8 8£8 HOH 0 8608 1I V丄 3H0 6 66ε 00 Ί SS0 99 £ Z6 ΌΙ 686 88 8 £ 8 HOH 0 8608 1I V 丄 3H
0 08'9£ 00 •ι SIZ ·9 οεο 11 •6 2£8 HOH 0 Z608 丄 3H0 08'9 £ 00 • ι SIZ9 οεο 11 • 6 2 £ 8 HOH 0 Z608 丄 3H
0 2ΖΊΡ 00 Ί οοο 'ε - ' 1 LIZ •61 928 HOH 0 9608 ( V丄 3H0 2ΖΊΡ 00 Ί οοο 'ε-' 1 LIZ61 928 HOH 0 9608 (V 丄 3H
0 Π "62 00 "L Ι Ή 8L2 'in— 628 '2- 9S8 HOH 0 9608 II V丄 3H0 Π "62 00" L Ι Ή 8L2 'in— 628' 2-9S8 HOH 0 9608 II V 丄 3H
0 LI ε 00 ,ι £Ζ8 '6L Ε90 '9- 68 •0 Π HOH 0 608 HIV丄 3H0 LI ε 00, ι £ Ζ8 '6L Ε90' 9- 68 • 0 Π HOH 0 608 HIV 丄 3H
0 00 ,ι 122 "12 8 0 Ί Πί •IS £S8 HOH 0 £608 MLLV丄 3H0 00, ι 122 "12 8 0 Πί Πί • IS £ S8 HOH 0 £ 608 MLLV 丄 3H
0 00 'ι ΕΖ ·01 9fr8 '9S 019 •l - 2£8 HOH 0 2608 1/ V丄 3H0 00 'ι ΕΖ01 9fr8' 9S 019l-2 £ 8 HOH 0 2608 1 / V 丄 3H
0 οε 00 Ί 816 ·91 9Ζ0 "92 in ■8ε LE8 HOH 0 L608 W1V丄 3H0 οε 00 Ί 816 · 91 9Ζ0 "92 in ■ 8ε LE8 HOH 0 L608 W1V 丄 3H
0 89'0£ 00 ,ι ε ' 8 t706 '61 189*02 0E8 HOH 0 0608 W1V丄 3H0 89'0 £ 00, ι ε '8 t706 '61 189 * 02 0E8 HOH 0 0608 W1V 丄 3H
0 ιε 'ο 00 Ί Γ8- 908 '21- I •9- 628 HOH 0 6808 i! V丄 3H0 ιε 'ο 00 Γ Γ8- 908 '21-I • 9- 628 HOH 0 6808 i! V 丄 3H
0 00 Ί 000· I 299 Ί 828 HOH 0 8808 IV丄 3H0 00 000 000 · I 299 Ί 828 HOH 0 8808 IV 丄 3H
0 00 Ί 0i6"8L i Ί- ' 9 LZ HOH 0 808 W丄 V丄 3H0 00 Ί 0i6 "8L i Ί- '9 LZ HOH 0 808 W 丄 V 丄 3H
0 86· ε 00 Ί 8'U- 989 Ό ιθΓζε 928 HOH 0 9808 W丄 V丄 3H0 86 ・ ε 00 Ί 8'U- 989 Ό ιθΓζε 928 HOH 0 9808 W 丄 V 丄 3H
0 00 Ί 98 - frZ8 Ί 6ΖΙΌ9 928 HOH 0 9808 W丄 V丄 3H0 00 Ί 98-frZ8 Ί 6ΖΙΌ9 928 HOH 0 9808 W 丄 V 丄 3H
0 90 00 ' Ί '99 H HOH 0 t^808 1N1V丄 3H0 90 00 'Ί '99 H HOH 0 t ^ 808 1N1V 丄 3H
0 W 00 Ί 90fr'9L 6W 'L- ·9ε 2 HOH 0 £808 IN丄 V丄 3H0 W 00 Ί 90fr'9L 6W 'L-9ε 2 HOH 0 £ 808 IN 丄 V 丄 3H
0 ·6£ 00 Ί W9 16 11 ■19 ZZ HOH 0 28080 6 £ 00 Ί W9 16 11 ■ 19 ZZ HOH 0 2808
0 00 Ί 19£*9 817 εοι •9 128 HOH 0 1808 丄 V丄 3H0 00 Ί 19 £ * 9 817 εοι • 9 128 HOH 0 1808 丄 V 丄 3H
0 ο·ζε 00 "1 9££7 09 '91 ι 028 HOH 0 0808 0 οζε 00 "1 9 ££ 7 09 '91 ι 028 HOH 0 0808
u u
0 £6·9ε 00 コ 0 £ 6.99 00
ι lit- "6 ε 19 ο- 910 6 L8 HOH O blUo 丄 V丄 dH ι lit- "6 ε 19 ο- 910 6 L8 HOH O blUo 丄 V 丄 dH
0 9·οε υυ 1 WS 968 ■8 is L8 HUH U o no コ u0 9 · οε υυ 1 WS 968 ■ 8 is L8 HUH U o no
0 ο 2ε 00 ,1 W92 9f •0 18 HOH 0 08 HIV丄ョ H0 ο 2ε 00, 1 W92 9f • 0 18 HOH 0 08 HIV
0 00 Ί 969.12 - ZLI "0- ZLQ "89 918 HOH 0 9108 W1V13H0 00 Ί 969.12-ZLI "0- ZLQ" 89 918 HOH 0 9108 W1V13H
0 00 '1 989 "U £8971 2Z •ει 918 HOH 0 S108 H1V13H0 00 '1 989 "U £ 8971 2Z • ει 918 HOH 0 S108 H1V13H
0 Z0'6S 00 ,1 ELL 7- ΖΖ^'Ζ 9丄 S ' 8 HOH 0 W1V13H0 Z0'6S 00, 1 ELL 7- ΖΖ ^ 'Ζ 9 丄 S' 8 HOH 0 W1V13H
0 LZ7E 00' '1 89S.9L f69"LL OIL "9- Π8 HOH 0 £108 H1V13H0 LZ7E 00 '' 1 89S.9L f69 "LL OIL" 9- Π8 HOH 0 £ 108 H1V13H
0 8Γ9ε 00 Ί 990"L2- 066 ' 6LL ■ε 218 HOH 0 ZL02 W1V13H0 8Γ9ε 00 Ί 990 ”L2-066 '6LL ■ ε 218 HOH 0 ZL02 W1V13H
0 29.1 00 '1 820'Π 68 - HZ •92 L18 HOH 0 U08 H1V13H 0 29.1 00 '1 820'Π 68-HZ92 L18 HOH 0 U08 H1V13H
(8170) ）8拏 (8170)) 8 Halla
Z 6 T CZ.600/COOZdf/X3d raeio請 O 98 表 8(その 49) Z 6 T CZ.600 / COOZdf / X3d raeio contract O 98 Table 8 (part 49)
HETATM 8104 0 HOH 844 33.231 26.922 10.767 1.00 42.16 0 HETATM 8105 0 HOH 845 7.493 -1.435 20.183 1.00 35.16 0 HETATM 8106 0 HOH 846 62.827 21.301 -3.335 1.00 34.17 0 HETATM 8107 0 HOH 847 -14.110 25.393 -0.870 1.00 43.45 0 HETATM 8108 0 HOH 848 8.113 -6.604 24.052 1.00 41.58 0 HETATM 8109 0 HOH 849 42.765 -1.929 -16.303 1.00 39.31 0 HETATM 8110 0 HOH 850 48.530 8.124 -5.597 1.00 32.90 0 HETATM 8111 0 HOH 851 8.105 8.600 -3.373 1.00 26.23 0 HETATM 8112 0 HOH 852 -6.274 4.312 2.510 1.00 48.13 0 HETATM 8113 0 HOH 853 39.678 1.719 -13.253 1.00 39.98 0 HETATM 8114 0 HOH 854 16.756 34.497 -13.670 1.00 42.44 0 HETATM 8115 0 HOH 855 41.151 -3.939 -15.905 1.00 46.57 0 HETATM 8116 0 HOH 856 -0.233 19.996 14.884 1.00 41.94 0 END HETATM 8104 0 HOH 844 33.231 26.922 10.767 1.00 42.16 0 HETATM 8105 0 HOH 845 7.493 -1.435 20.183 1.00 35.16 0 HETATM 8106 0 HOH 846 62.827 21.301 -3.335 1.00 34.17 0 HETATM 8107 0 HOH 847 -14.110 25.393 -0.870 1.00 43.108 0 HOH 848 8.113 -6.604 24.052 1.00 41.58 0 HETATM 8109 0 HOH 849 42.765 -1.929 -16.303 1.00 39.31 0 HETATM 8110 0 HOH 850 48.530 8.124 -5.597 1.00 32.90 0 HETATM 8111 0 HOH 851 8.105 8.600 -3.373 1.00 26.23 0 HETATM 8112 HOH 852 -6.274 4.312 2.510 1.00 48.13 0 HETATM 8113 0 HOH 853 39.678 1.719 -13.253 1.00 39.98 0 HETATM 8114 0 HOH 854 16.756 34.497 -13.670 1.00 42.44 0 HETATM 8115 0 HOH 855 41.151 -3.939 -15.905 1.00 46.57 0 HETATM 8 856 -0.233 19.996 14.884 1.00 41.94 0 END

Claims

請 求 の 範 囲 The scope of the claims
1. 天然トリプターゼまたはリコンビナントトリプターゼを未変性の状態で糖鎖 切断処理して得られる、 SDS— PAGEでクマシ一染色により単一バンドとし て検出されるトリプターせ。 1. A trypter detected as a single band by Coomassie staining on SDS-PAGE, which is obtained by cleavage of native tryptase or recombinant tryptase in a native state with sugar chains.
2. 前記糖鎖切断処理がエンド一 )3— N—ァセチルダルコサミニダーゼ （ E n d o— /3— N— a c e t y 1 g 1 u c o s am i n i d a s e ) による処理 である請求項 1に記載のトリプ夕一ゼ。  2. The trip ichiichi according to claim 1, wherein the sugar chain cleavage treatment is treatment with endo-) 3-N-acetyldarcosaminidase (Endo / 3 / 3-N-acety 1 g 1 ucos am inidase). Ze.
3. 糖鎖切断処理する前と比較して酵素活性が 5 0 %以上維持されている 請求項 1に記載のトリプターゼ。  3. The tryptase according to claim 1, wherein the enzyme activity is maintained at 50% or more as compared to before the sugar chain cleavage treatment.
4. SD S— PAGEによる分子量が約 3 3 kD aである請求項 1に記載の トリプターゼ。  4. The tryptase according to claim 1, which has a molecular weight of about 33 kDa according to SDS-PAGE.
5. シッティングドロップ蒸気拡散法にて 2ヶ月以内で結晶化できる請求項 1に 記載のトリプタ一ゼ。  5. The tryptase according to claim 1, which can be crystallized within two months by a sitting drop vapor diffusion method.
6. 天然トリプターゼまたはリコンビナントトリプターゼを、 未変性の状態で糖 鎖切断酵素で処理する工程を含むことを特徴とする、 糖鎖切断処理する前と比較 して酵素活性が 5 0 %以上維持されている、 糖鎖が実質的に切断された トリプターゼの製造方法。 6. A step of treating native tryptase or recombinant tryptase in a native state with a sugar chain-cleaving enzyme, wherein the enzyme activity is maintained at 50% or more compared to that before the sugar chain-cleaving treatment. A method for producing a tryptase having a sugar chain substantially cleaved.
7. 糖鎖切断酵素が、 エンド— jS— N—ァセチルダルコサミニダーゼ （En d o - β-Ν- a c e t y l g l u c o s am i n i d a s e) である請求項 6に記 載の製造方法。  7. The method according to claim 6, wherein the sugar chain-cleaving enzyme is endo-jS-N-acetyldarcosaminidase (Endo-β-Ν-acetylgluccosaminidanse).
8. 糖鎖切断酵素で処理する工程が、 キレート剤存在下、 pH 5. 0〜pH 8. The step of treating with a sugar chain-cleaving enzyme is performed in the presence of a chelating agent,
7. 0の緩衝液中で 30〜40°Cの条件で、 糖鎖切断酵素で処理することを特徴 とする工程である請求項 6に記載の製造方法。 7. The production method according to claim 6, which is a step of treating with a sugar chain-cleaving enzyme in a buffer of 7.0 at 30 to 40 ° C.
9. 天然トリプ夕一ゼまたはリコンビナントトリプターゼを、 未変性の状態で糖 鎖切断酵素で処理して、 結晶化することを特徵とするトリプターゼ結晶の製造方 法。  9. A method for producing a tryptase crystal, which comprises crystallizing a natural tryptic enzyme or recombinant tryptase in a native state with a sugar chain-cleaving enzyme to crystallize the same.
10. 天然トリプ夕一ゼまたはリコンビナントトリプターゼを、 未変性の状態で 糖鎖切断酵素で処理した後、 トリプ夕一ゼとァフィニティを持つ物質との複合体 を作成し、 結晶化することを特徴とするトリプターゼと、 トリプタ一ゼと ァフィ二ティを持つ物質との複合体結晶の製造方法。  10. After treating native trypticase or recombinant tryptase with a carbohydrate-cleaving enzyme in a native state, a complex of trypticase and a substance having affinity is formed and crystallized. A method for producing a composite crystal of tryptase and a substance having tryptase and affinity.
11. 前記結晶化において、 ポリオ一ルを沈殿剤に用いるシッティングドロップ 蒸気拡散法により、 結晶化する工程であることを特徴とする請求項 9または 10 に記載の結晶の製造方法。 11. The method for producing crystals according to claim 9, wherein the crystallization is a step of crystallization by a sitting drop vapor diffusion method using a polyol as a precipitant.
12. 請求項 1に記載のトリプターゼと、 該トリプターゼにァフィニティを有す る物質との複合体結晶。  12. A composite crystal of the tryptase according to claim 1 and a substance having an affinity for the tryptase.
13. トリプ夕一ゼと、 N— [ 2― CN- [ 3一 [4 - (アミノメチル) フエニル] プロピル] ァミノ] ェチル] 一 2—ナフタレンスルホンアミドまたは その塩との複合体結晶。  13. Complex crystals of tryptic and N- [2-CN- [3-1- [4- (aminomethyl) phenyl] propyl] amino] ethyl] -12-naphthalenesulfonamide or a salt thereof.
14. トリプターゼと、 N— [2— [N- [3— [4- (アミノメチル) フエ二 ル] プロピル] 一 N—メチルァミノ] ェチル] —2—べンゾ [b] チォフェン力 ルポキサミドまたはその塩との複合体結晶。  14. Tryptase and N— [2 -— [N- [3 -— [4- (aminomethyl) phenyl] propyl] -1-N-methylamino] ethyl] —2-benzo [b] thiophene lipoxamide or its Complex crystal with salt.
1 5. 以下の工程を含むことを特徴とするトリプターゼ活性を阻害する化合物の スクリーニング方法 2 0 1 5. A method for screening a compound that inhibits tryptase activity, comprising the following steps: 2 0
①糖鎖切断したトリプターゼとあらかじめトリプ夕一ゼ活性を阻害することが わかつている化合物との複合体結晶を作成する工程 (1) A process for preparing a complex crystal of a trypticase with a sugar chain cleaved and a compound that is known to inhibit trypase activity in advance
②前記作成した結晶の三次元構造を解析し、 糖鎖切断したトリプ夕ーゼと前記 化合物との相互作用から、 トリプタ一ゼ活性を阻害する化合物のフアルマコフォ ァを作成し、 トリプタ一ゼ活性を阻害する化合物をバ一チャルで選択する工程 (2) Analyze the three-dimensional structure of the prepared crystal, and make a pharmacophore of a compound that inhibits tryptase activity from the interaction between the sugar chain-cleaved trypsinase and the compound. The step of selecting the compound to be inhibited by virtual
③前記バーチャルで選択した化合物をリアルで用意する工程、 及び (3) a step of preparing the virtual selected compound in real time, and
④用意した前記化合物のトリプターゼ活性に対する影響を in vi troの系および ノまたは in vivo の系にて測定する工程。  (4) A step of measuring the effect of the prepared compound on the tryptase activity in an in vitro system and in an in vivo or in vivo system.
1 6 . 表 1に記載の条件 1 ~ 4をすベて満たすフアルマコフオアをコン ピュ一夕一ソフトウエアに供用することにより、 当該フアルマコフォアを満たす ヒト ]3トリプタ一ゼ活性を阻害する化合物をバーチャルで選択する工程を含むこ とを特徴とする、 ヒト /3トリプ夕一ゼ活性を選択的に阻害する化合物のスクリ一 ニング方法。  16. By applying to a computer overnight software a pharmacophore that satisfies all of the conditions 1 to 4 described in Table 1, a compound that inhibits the human] 3 tryptase activity that satisfies the pharmacophore can be virtually produced. A method for screening a compound that selectively inhibits human / 3-tripase activity, comprising a step of selecting.
表 Ί  Table Ί
ヒト/ Sトリブタ一ゼのァ  Human / S
条件 化合物の官能基 相互作用様式 · 位置  Condition Compound functional group Interaction modePosition
ミノ酸残基  Amino acid residue
Asp189側鎖の酸素原子を中心として 3.21 3.21 around the oxygen atom in the side chain of Asp189
1 Asp189 窒素原子 イオン結合 ±0.5 A以内に g素原子が位置すること 1 Asp189 Nitrogen atom Ion bond g element must be located within ± 0.5 A
Gln192, Trp215, Gly219の C d 'からの距離 Distance of Gln192, Trp215, Gly219 from C d '
Gln192, Τ 215, がそれぞれ 5.2 ± 1.4 .9 ± 1.4Gln192, Τ215, respectively 5.2 ± 1.4.9 ± 1.4
2 疎水性官能基 疎水性相互作用 A、 3 A、 6.1土 2 Hydrophobic functional group Hydrophobic interaction A, 3 A, 6.1 soil
Gly219 1.4 Aで形成される空間に疎水性官能基の 重心の重心が位置すること  The center of gravity of the hydrophobic functional group is located in the space formed by Gly219 1.4 A
Ala97主鎖の窒素原子より 2.9±0.5 A以2.9 ± 0.5 A or less from nitrogen atom of Ala97 main chain
3 Ala97, Gln98 水素結合受容基 水素結合 内、あるいは Gln98の N ε原子より 3·2±0.5 3 Ala97, Gln98 Hydrogen bond acceptor group Within hydrogen bond or 3.2 ± 0.5 from Nε atom of Gln98
Α以内に水素結合受容基が位置すること  Hydrogen bond accepting group located within Α
Tyr95, Thr96,隣接す Tyr95, Thr96, adjacent
Tyr95, Thr96および隣接するトリブターゼの るトリブターゼ Glu217  Tributase with Tyr95, Thr96 and adjacent trybutase Glu217
Glu217の C aからの距離がそれぞれ 6.S± (隣接するトリブタ一ゼ  The distance of Glu217 from Ca is 6.S ±
芳香環もしくは環状炭 疎水性相互作用また 1.4  Aromatic or cyclic charcoal Hydrophobic interaction or 1.4
4 A、 5.1 ± 1.4 A、 7.7 ± 1.4 Aで形成される Glu217 : 4量体を形成  Glu217 formed at 4 A, 5.1 ± 1.4 A, 7.7 ± 1.4 A: Form tetramer
化水素 は水素結合 空間に芳香環もしくは環状炭化水素の重 するトリブターゼにお  Hydrogen is bound to tributase in which aromatic or cyclic hydrocarbons overlap in the hydrogen bonding space
心がトリブタ一ゼと立体障害を起こさずに いて、隣接するトリブ  The heart is not sterically hindered by trybuta
タ一ゼの Glu217) 存在すること 2 0 2 Gaze 217) 2 0 2
1 7 . 表 2に記載の条件 1〜 4をすベて満たすフアルマコフォアをコン ピュー夕一ソフトウェアに供用することにより、 当該フアルマコフォアを満たす ヒト i3トリプ夕一ゼ活性を阻害する化合物をバーチャルで選択する工程を含むこ とを特徴とする、 ヒト /3トリプターゼ活性を選択的に阻害する化合物のスクリ— ニング方法。  17. By applying a pharmacophore that satisfies all of the conditions 1 to 4 described in Table 2 to the computer software, a compound that inhibits the human i3 trypase activity that satisfies the pharmacophore is virtually selected. A method for screening a compound that selectively inhibits human / 3 tryptase activity, comprising a step of:
Figure imgf000203_0001
Figure imgf000203_0001
1 8 . 以下の工程を含むことを特徴とするヒト /3トリプターゼ活性を選択的に阻 害する化合物のドラッグデザィン方法 18. A method for drug designing a compound that selectively inhibits human / 3 tryptase activity, comprising the following steps:
①表 1に記載のフアルマコフォアの各条件に対応する官能基を有する 各フラグメント群を作成する工程。  (1) A process of preparing each fragment group having a functional group corresponding to each condition of the pharmacophore described in Table 1.
②①で作成した各フラグメント群より一つずつ選  ② Select one by one from each fragment group created in ①
合させて、 化合物をモデル構築する工程。 2 0 3 Combined to build a model of the compound. 2 0 3
1 9 . 以下の工程を含むことを特徴とするヒト^トリプターゼ活性を選択的に阻 害する化合物のドラッグデザィン方法  1 9. A method for drug design of a compound that selectively inhibits human ^ tryptase activity, comprising the following steps:
①表 2に記載のフアルマコフオアの各条件に対応する官能基を有する 各フラグメント群を作成する工程。  (1) A step of creating each fragment group having a functional group corresponding to each condition of the pharmacophore described in Table 2.
②①で作成した各フラグメント群より一つずつ選択された各フラグメントを結 合させて、 化合物をモデル構築する工程。  (2) A process in which each fragment selected one by one from each fragment group created in (1) is combined to construct a compound model.
2 0 . ヒト トリプ夕一ゼ活性を選択的に潜在的に阻害しうる化合物からなる化 合物ァレイの作成方法であり、 表 1に記載のフアルマコフォアをコンピュータ一 ソフトウエアに供用することにより前記フアルマコフォアを満たすヒト トリプ 夕一ゼ活性を選択的に阻害する化合物をバ一チャルで選択し、 選択した化合物を リアルで用意して組み合わせて、 化合物アレイを作成する方法。  20. A method for preparing a compound array comprising a compound capable of selectively and potentially inhibiting human trypticase activity, and applying the pharmacophore described in Table 1 to computer software to obtain the pharmacophore. A method for selecting a compound that selectively inhibits human trypticase activity in a virtual manner, preparing the selected compounds in real time, and combining them to create a compound array.
2 1 . ヒト /3トリプタ一ゼ活性を選択的に潜在的に阻害しうる化合物アレイの作 成方法であり、 表 2に記載のフアルマコフォアをコンピュータ一ソフトウエアに 供用することにより前記フアルマコフォアを満たすヒト i3トリプターゼ活性を選 択的に阻害する化合物をバーチャルで選択し、 選択した化合物をリアルで用意し て組み合わせて、 化合物アレイを作成する方法。 21. A method for preparing a compound array capable of selectively and potentially inhibiting human / 3 tryptase activity, and applying the pharmacophore described in Table 2 to computer software to satisfy the pharmacophore. A method in which compounds that selectively inhibit i3 tryptase activity are virtually selected, and the selected compounds are prepared in real time and combined to form a compound array.
2 2 . 表 3および表 4に記載のフラグメント群より構築した一般式 S , - L 一 A rの化合物デ一夕ベースを、 表 1または表 2に示すフアルマコフォアをコン ピューターソフトウエアに供用することにより選択される、 ヒト /3トリプターゼ 活性を選択的に潜在的に阻害しうる化合物のライブラリー。
Figure imgf000205_0001
22. Use of the compound of the general formula S, -L-Ar constructed from the fragment groups described in Tables 3 and 4 and the pharmacophore shown in Table 1 or Table 2 for computer software A library of compounds that can selectively and selectively inhibit human / 3 tryptase activity.
Figure imgf000205_0001
s  s
JV ""- Ί S ー  JV ""-Ί S ー
ε拏  ella
C.600/C00Zdf/X3d tzmo請 表 4 C.600 / C00Zdf / X3d tzmo contract Table 4
般  General
s  s
_し  _
A
Figure imgf000206_0001
A
Figure imgf000206_0001
Figure imgf000206_0002
Figure imgf000206_0002
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