CN104739820B - Small molecule inhibitor and application thereof to inhibiting ornithine decarboxylase (ODC) - Google Patents
Small molecule inhibitor and application thereof to inhibiting ornithine decarboxylase (ODC) Download PDFInfo
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Abstract
The invention belongs to the field of biomedicine and relates to a small molecule inhibitor of ornithine decarboxylase (ODC) and an application thereof. A novel small molecule inhibitor aiming at ODC is found through computer-aided high-throughput medicine screening. Verification of the effects of the novel small molecule inhibitor finds that the novel small molecule inhibitor has good inhibiting effects on ODC and can be especially used for inhibiting human-derived ODC, preventing, treating and diagnosing tumor diseases and pathogenic microorganism infection and developing and preparing tumor medicines or medicines against pathogenic microorganism infection.
Description
Technical field
The present invention relates to ODC Ornithine decarboxylase (Ornithine decarboxylase;ODC micromolecular inhibitor) and its
Application and in particular to the micromolecular inhibitor of people source ODC Ornithine decarboxylase and its suppression and killing tumor cell in application.
Background technology
Protein is one of main constituents of organism, is the main matter completing various vital movements.Various
In protein, protease is most important to vital movement, and the internal biochemical reaction process of nearly all biology is all entered by protease
Row catalysis.The activity of biological various in vivo protease has strict regulatory mechanism, once its regulatory mechanism goes wrong, causes
The hyperactivity of protease, too low or complete deactivation, all can cause corresponding various diseases.Therefore, adjusted by medicine
The activity of control protease, so as to recovering and being maintained at normal level, has very important theory significance and realistic meaning.To tie
Drug design based on structure, is very important means of the medicine with protein as target for the design.
Polyamines (polyamines) is the cation micro molecule of the positively charged that a class produces from amino acid metabolism, in all lifes
All exist in object, cell growth, differentiation, survival and natural biological function etc. are all indispensable.The many positive charges of polyamines band
Characteristic, enable them to make by forming electrostatic with negatively charged biomacromolecule (DNA, RNA, protein, cell membrane etc.)
With thus regulation and control biological process widely, being configured to including chromosome knob, DNA synthesizes and stable, DNA replication dna, transcription
With translation, protein phosphorylation, the regulation and control of ribosome generation, ion channel and film surface receptor, free radical scavenging etc..Natural
Polyamines has many kinds.In mammal, naturally occurring have three kinds, i.e. putrescine (putrescine), spermidine
(spermidine), spermine (spermine), they are essential to mammal normal growth and growth.Because polyamines has
Important biological function, its Intracellular levels is subject to strict regulating and controlling.In the cell of Fast-propagation, such as tumor cell is many
Amine level and ODC expression also can rise and lack of proper care.Polyamine level raise, along with cell proliferation accelerate, apoptosis reduce, with
And the expression of tumor-infiltrated and metastasis related gene rise high.Therefore, the regulation and control of polyamines, become oncotherapy and medicine grinds
Send out one of important means.
The starting material of Polyamine Metabolism is ornithine (ornithine), and it is arginine in ornithine cycle (urea
Cycle the product being catalyzed by arginase (arginase) in).ODC is first enzyme of polyamines route of synthesis, catalysis from
Ornithine (ornithine) arrives the reaction of putrescine, and this step catalytic reaction is also a rate-limiting step of polyamines route of synthesis.Cause
This, synthesize ODC inhibitor, the generation of suppression putrescine, is a currently in popular attention oncotherapy approach.Simultaneously as it is sick
Pathogenic microorganism is also required to normal polyamine level, and ODC inhibitor also becomes for pathogenic microorganism (as led to african trypanosomiasis
Trypanosoma bocagei) important target.
Currently, the inhibitor DFMO (alpha-difluoromethyl ornithine) of ODC has been used for clinic, the chemotherapy of auxiliary cancer.
But it is weaker with the binding ability of ODC, and activity is very high, and due to being the suicide inhibitor forming covalent bond with ODC, poison
Side effect is very big.Therefore, it is highly desirable to develop the ODC new inhibitor with more preferable effect.
Content of the invention
The purpose of the present invention is by computer assisted high-flux medicaments sifting, provides a kind of new little for ODC
Molecule inhibitor, is applied to the inhibitor of ODC Ornithine decarboxylase, may can be used for preparation treatment tumor, pathogenic microorganism
The medicine of infection.It is specially:
A kind of micromolecular inhibitor is it is characterised in that the structural formula of this micromolecular inhibitor is:
Wherein, R1For ortho position or meta or para position.R1Arrcostab, alkyl ether, alkyl aldehydes or alkyl ketone.
Described R1Including
The structural formula of further preferably this micromolecular inhibitor is:
Using application in suppression ODC Ornithine decarboxylase (ODC) for any one micromolecular inhibitor above-mentioned.
Using application in preparation tumor for any one micromolecular inhibitor above-mentioned.
Using application in preparation treatment cause pathogeny imcrobe infection medicine for the described micromolecular inhibitor.
The method above-mentioned micromolecular inhibitor being used for suppress ODC Ornithine decarboxylase (ODC), comprises the steps:
1) structure of ODC prokaryotic expression plasmid
By the gene order of ODC, by BamH I and Xho I restriction enzyme site, it is inserted in pET28a plasmid, constructs
PET28a-hODC plasmid, through DNA sequencing checking;
2) expression of ODC albumen
By step 1) the pET28a-hODC plasmid that builds passes through CaCl2Method, is transformed in e. coli strain bl21, leads to
Cross kanamycin to be screened, then by the bacterial strain of growth on the Luria-Bertani containing kanamycin (LB) culture plate,
Be seeded in the LB fluid medium containing kanamycin, 37 DEG C, 250rpm cultivates to exponential phase, then adds isopropyl
Thiogalactoside (IPTG) to 0.5mM, in 28 DEG C of abduction deliverings 4 hours, finally, is collected by centrifugation antibacterial;
3) purification of ODC albumen
By step 2) the middle antibacterial collected, use lysate Eddy diffusion, then cell cracking is carried out by ultrasonic method, then
By lysate at 4 DEG C, 12000 turns/min, after centrifugation, retain supernatant;Finally supernatant is utilized Ni-NTA His label protein to tie
Close filler to be combined and purification, obtain ODC albumen, the elution buffer of ODC albumen is 50mM trishydroxymethylaminomethane
(Tris)/HCl, pH 8.0,300mM NaCl, 1mM DTT, 100mM imidazoles (imidazole);
4) Activity determination of ODC albumen
In EP pipe, add 400uL substrate reactions mixture, the ODC albumen of 50ug, after mixing, EP pipe is placed on 37 DEG C
30min in water-bath;Add the trichloroacetic acid terminating reaction of 400uL 10%, room temperature is centrifuged 5000rpm, 5min, then takes out
100uL supernatant, is mixed with the NaOH solution of 200uL 4mol/L, adds 400uL n-amyl alcohol, is sufficiently mixed, and 2000rpm is centrifuged
5min, then upper liquid 200uL is transferred in new EP pipe, add the sodium tetraborate mixing that 200uL0.1mol/LpH is 8.0 all
Even, addition 200uL10 mmol/L trinitro-benzene-sulfonic acid mixing is abundant, addition 400uL DMSO, is sufficiently mixed 1min, 3000rpm
Centrifugation 5min;Finally take out upper liquid in 96 orifice plates, detect the light absorption value at 426nm with microplate reader, obtain not enzyme-added OD
Value
5) detection of the inhibitory activity to ODC albumen for the inhibitor
According to step 4) described in method, add 400uL substrate reactions mixture after, immediately add ornithine decarboxylation
The micromolecular inhibitor of enzyme, the same step 4) of subsequent operation;
ODC suppression ratio is calculated by below equation:
Comparison is poor=plus micromolecular inhibitor matched group mean OD value-do not add micromolecular inhibitor matched group mean OD value,
Wherein matched group is in step 5) in add inhibitor be DFMO inhibitor;
Experiment is poor=plus micromolecular inhibitor experimental group mean OD value-do not add the average OD of micromolecular inhibitor experimental group group
Value;
ODC suppression ratio=[(compareing poor-experiment poor)/comparison is poor] × 100%.
Described step 3) described in lysate be 50mM trishydroxymethylaminomethane (Tris)/HCl, pH 8.0,
300mM NaCl, 1mM DTT, the mixed liquor of 1mM PMSF, 5mM imidazoles (imidazole).
Described step 4) in substrate reactions mixture be 150mM pH be 7.1 phosphate buffer (PBS) in
Dissolving 17.57ul beta -mercaptoethanol, 55.84mg 1.5mM EDTA disalt sodium, 75nM pyridoxal 5-phosphate (PLP) liquid storage, 2mM bird
Propylhomoserin hydrochlorate.
Described ODC Ornithine decarboxylase behaviour source ODC Ornithine decarboxylase, inhuman source ODC Ornithine decarboxylase or with people source ornithine
The putrescine substrate of decarboxylase and the protein of pyridoxal 5-phosphate binding site very high homology.
According to above scheme, first with Pocket pharmaceutical grade protein pocket analysis software, with the crystal structure of people source ODC
Based on, its putrescine substrate and PLP ligand binding pocket are analyzed, and produce the theoretical mould of this protein pocket
Type.Then, using protein docking procedure DOCK, 190,000 small molecules in SPECS small-molecule drug storehouse are docked to above-mentioned
In protein bag model, and filter out at least contain 15 non-hydrogen heavy atoms, at least formed 2 hydrogen bonds, at least one hydrophobic in
The heart, the small molecule less than -10 for the docking marking.Again to above-mentioned small molecule further with protein-small molecule docking procedure
Autodock, is docked to successively again in above-mentioned protein pocket, is further docked calculating, finally pick out docking
The small molecule less than -7 for the marking.
The present invention also provides a kind of compositionss, and it is little that the present invention that it contains to suppression ODC Ornithine decarboxylase effective dose provides
Molecule inhibitor or its analog and pharmaceutically useful carrier.Preferably described compositionss are pharmaceutical compositions, and it contains to controlling
Treat micromolecular inhibitor or its analog and the pharmaceutically useful carrier that the present invention of effective dose provides.More preferably described medicine
Compositionss are the pharmaceutical compositions of the disease of suppression generation response for the treatment of or prevention ODC Ornithine decarboxylase (ODC), wherein bird ammonia
Acid decarboxylase (ODC) preferably humanized's ODC Ornithine decarboxylase (ODC);Also include containing for the suppression preventing and treating ODC Ornithine decarboxylase
Produce micromolecular inhibitor or its analog and the pharmaceutically useful carrier that the present invention of the condition effective amount of response provides.
The micromolecular inhibitor of the present invention or its analog and above-mentioned composition can be used for suppressing ODC Ornithine decarboxylase
(ODC), preferred humanized's ODC Ornithine decarboxylase (ODC), wherein said suppression is therapeutic purposes or non-treatment purpose.Preferably this
Bright micromolecular inhibitor or its analog are used for the medicine that preparation suppresses ODC Ornithine decarboxylase (ODC), preferably humanized bird ammonia
Acid decarboxylase (ODC).Therefore present invention also offers suppression ornithine decarboxylase activity method, the method include to need press down
The object of ODC Ornithine decarboxylase (ODC) processed applies the micromolecular inhibitor of the present invention or its analog or above-mentioned group of effective dose
Compound, wherein said suppression is therapeutic purposes or non-treatment purpose.
Present invention also offers treating the method that the suppression to ODC Ornithine decarboxylase produces the disease of response, the method includes
To individual suppression ODC Ornithine decarboxylase (the preferably humanized applying prevention or the upper effective dose for the treatment of needing this treatment or prevention
ODC Ornithine decarboxylase (ODC)) the micromolecular inhibitor of the present invention or its analog or above-mentioned composition.
The micromolecular inhibitor of the present invention or its analog can be used for preparing the suppression generation to ODC Ornithine decarboxylase for the treatment
The medicine of the disease of response or pharmaceutical composition, wherein ODC Ornithine decarboxylase (ODC) or its analog suppression ODC Ornithine decarboxylase
Activity, described disease includes tumor or cause pathogeny imcrobe infection, preferably above-mentioned tumor.Protozoan infection refers to ornithine decarboxylation
The suppression of enzyme produces tumor disease or the cause pathogeny imcrobe infection disease of response.
Brief description
Fig. 1 is the inhibition to people source ODC Ornithine decarboxylase for the micromolecular inhibitor of embodiment 1.
Fig. 2 is that embodiment 1 adopts mtt assay to detect the fragmentation effect to tumor cell for the inhibitor.
Fig. 3 is the combination model with people source ODC Ornithine decarboxylase for the micromolecular inhibitor of embodiment 1.
Specific embodiment
Embodiment 1
Involved micromolecular inhibitor is:3-Benzoylamino-benzoic acid ethyl ester, structural formula
As shown in the figure.
Activity test method is as follows:
1. the structure of people source ODC prokaryotic expression plasmid
By the gene order of people source ODC, by BamH I and Xho I restriction enzyme site, it is inserted in pET28a plasmid, build
Go out pET28a-hODC plasmid, through DNA sequencing checking.
The gene order of people source ODC:
atgaacaactttggtaatgaagagtttgactgccacttcctcgatgaaggttttactgccaaggacattctggacca
gaaaattaatgaagtttcttcttctgatgataaggatgccttctatgtggcagacctgggagacattctaaagaaac
atctgaggtggttaaaagctctccctcgtgtcacccccttttatgcagtcaaatgtaatgatagcaaagccatcgtg
aagacccttgctgctaccgggacaggatttgactgtgctagcaagactgaaatacagttggtgcagagtctgggggt
gcctccagagaggattatctatgcaaatccttgtaaacaagtatctcaaattaagtatgctgctaataatggagtcc
agatgatgacttttgatagtgaagttgagttgatgaaagttgccagagcacatcccaaagcaaagttggttttgcgg
attgccactgatgattccaaagcagtctgtcgtctcagtgtgaaattcggtgccacgctcagaaccagcaggctcct
tttggaacgggcgaaagagctaaatatcgatgttgttggtgtcagcttccatgtaggaagcggctgtaccgatcctg
agaccttcgtgcaggcaatctctgatgcccgctgtgtttttgacatgggggctgaggttggtttcagcatgtatctg
cttgatattggcggtggctttcctggatctgaggatgtgaaacttaaatttgaagagatcaccggcgtaatcaaccc
agcgttggacaaatactttccgtcagactctggagtgagaatcatagctgagcccggcagatactatgttgcatcag
ctttcacgcttgcagttaatatcattgccaagaaaattgtattaaaggaacagacgggctctgatgacgaagatgag
tcgagtgagcagacctttatgtattatgtgaatgatggcgtctatggatcatttaattgcatactctatgaccacgc
acatgtaaagccccttctgcaaaagagacctaaaccagatgagaagtattattcatccagcatatggggaccaacat
gtgatggcctcgatcggattgttgagcgctgtgacctgcctgaaatgcatgtgggtgattggatgctctttgaaaac
atgggcgcttacactgttgctgctgcctctacgttcaatggcttccagaggccgacgatctactatgtgatgtcagg
gcctgcgtggcaactcatgcagcaattccagaaccccgacttcccacccgaagtagaggaacaggatgccagcaccc
tgcctgtgtcttgtgcctgggagagtgggatgaaagccacagagcagcctgtgcttcggctagtattaatgtgtag
The above-mentioned people source ODC sequence that we use, with data base (http://www.ncbi.nlm.nih.gov/
Nuccore/NM_002539.1 the sequence in) has a base change, and (C of square frame labelling is T in database sequence, corresponding
Aminoacid cysteine is changed into from arginine), but do not affect its activity.
2. the expression of people source ODC albumen
Above-mentioned pET28a-hODC plasmid is passed through CaCl2Method, is transformed in e. coli strain bl21, and by card, that is mould
Element is screened.It is seeded to the bacterial strain of growth on the Luria-Bertani containing kanamycin (LB) culture plate containing card
In the LB fluid medium of that mycin, 37 DEG C, 250rpm cultivate to exponential phase, then add IPTG (isopropylthio half
Lactoside) to 0.5mM, in 28 DEG C of abduction deliverings 4 hours.Finally, antibacterial is collected by centrifugation.
3. the purification of people source ODC albumen
By the antibacterial of above-mentioned collection, with lysate (50mM Tris/HCl, pH 8.0,300mM NaCl, 1mM DTT, 1mM
PMSF, 5 mM imidazole.) Eddy diffusion, then cell cracking is carried out by ultrasonic method.Then by lysate 4 DEG C,
After 12000 leave the heart, retain supernatant.Supernatant is combined with reference to filler and purification using Ni-NTA His label protein, people
The elution buffer of source ODC albumen is 50mM Tris/HCl, pH 8.0,300mM NaCl, 1mM DTT, 100mM
imidazole.
4. the Activity determination of people source ODC albumen
In the EP pipe of 1.5mL, add (the dissolving in 150mM PBS (pH 7.1) of 400uL substrate reactions mixture
17.57ul beta -mercaptoethanol, 55.84mg 1.5mM EDTA disalt sodium, 75nM PLP liquid storage, 2mM dlornithine hydrochloride).So
Afterwards, add the ODC albumen of 50ug.After mixing, EP pipe is placed on 30min in 37 DEG C of water-baths.It is subsequently adding the three of 400uL 10%
Monoxone terminating reaction.Room temperature is centrifuged 5000rpm, 5min.Take out 100uL supernatant, mix with the NaOH solution of 200uL 4mol/L
Close, add 400uL n-amyl alcohol, be sufficiently mixed.2000rpm is centrifuged 5min, and upper liquid 200uL is transferred in new EP pipe,
200uL sodium tetraborate (0.1mol/L, pH8.0) is added to be sufficiently mixed.It is subsequently adding 200uL trinitro-benzene-sulfonic acid (10mmol/
L), it is sufficiently mixed.Add 400uL DMSO, be sufficiently mixed 1min.3000rpm is centrifuged 5min.Take out upper liquid to 96 orifice plates
In, detect the light absorption value at 426nm with microplate reader.
5. the detection of the inhibitory activity of inhibitor on human source ODC albumen
In above-mentioned Activity determination step, after adding 400uL substrate reactions mixture, add small-molecule drug immediately and mix
Close.Subsequent step is the same.
ODC suppression ratio is calculated by below equation
Comparison poor=enzyme-added matched group mean OD value-not enzyme-added matched group mean OD value
Experiment poor=enzyme-added experimental group mean OD value-not enzyme-added experimental group group mean OD value
ODC suppression ratio=[(compareing poor-experiment poor)/comparison is poor] × 100%.
The inhibition of this micromolecular inhibitor obtaining according to the method described above is as shown in figure 1, as can be seen from the figure exist
During 1mM, this medicine can suppress the activity of ODC, and its rejection ability is suitable with the DFMO of 2.5mM.
The fragmentation effect to tumor cell for the inhibitor is detected using mtt assay
A549 cell is seeded in 96 porocyte culture plates, 2000 cells/well of inoculum density, culture medium is RPMI-
1640,10% calf serum, 1% chain/penicillin, volume 100uL/ hole.After 37 DEG C of cell culture incubators are cultivated 24 hours, plus
Enter small-molecule drug or the culture medium that 100uL RPMI-1640 dilutes.After continuing culture 60 hours, suck culture medium, add
After 100uL MTT (final concentration 250ug/mL), continue culture 4 hours.Then suck culture fluid, add 150uL DMSO, shaking
Low-speed oscillation 15min on bed, makes crystal fully dissolve.Finally, read the light absorption value at 490nm using microplate reader.
The mtt assay that obtains according to the method described above detect inhibitor to the fragmentation effect of tumor cell as shown in Fig. 2 from figure
It can be seen that in 2.5mM, 1mM, 25uM, this medicine can suppress and killing tumor cell, but ability is very weak in 0.25uM.
The combination model figure of above-mentioned micromolecular inhibitor and ODC is shown in Fig. 3, it can be seen that black is the same of ODC
The dimeric chain in source, Lycoperdon polymorphum Vitt is another chain.This small-molecule drug is shown as stick model, in conjunction with dimeric interface
In pocket.Around small-molecule drug, 4 angstroms of in the distances may participate in the residue marker display side chain interacting.
Embodiment 2
Involved micromolecular inhibitor is:N- (3-Acetyl-phenyl)-benzamide, structural formula is as shown in the figure:
Embodiment 3
Involved micromolecular inhibitor is:N- (4-Propoxy-phenyl)-benzamide, structural formula is as shown in the figure:
Embodiment 4
Involved micromolecular inhibitor is:3- (2-Benzoylamino-phenyl)-propionic acid, structure
Formula is as shown in the figure:
Embodiment 5
Involved micromolecular inhibitor is:3-Benzoylamino-benzoic acid methyl ester, structure
Formula is as shown in the figure:
Claims (6)
1. a kind of application on the medicine of preparation suppression ODC Ornithine decarboxylase (ODC) for micromolecular inhibitor is it is characterised in that be somebody's turn to do
The structural formula of micromolecular inhibitor is:
2. a kind of application in preparation tumor of micromolecular inhibitor is it is characterised in that this micromolecular inhibitor
Structural formula is:
3. a kind of screening micromolecular inhibitor has the method for suppression ODC Ornithine decarboxylase (ODC) activity it is characterised in that including
Following steps:
(1) structure of ODC prokaryotic expression plasmid
By the gene order of ODC, by BamH I and Xho I restriction enzyme site, it is inserted in pET28a plasmid, constructs
PET28a-hODC plasmid, through DNA sequencing checking;
(2) expression of ODC albumen
The pET28a-hODC plasmid that step (1) is built passes through CaCl2Method, is transformed in e. coli strain bl21, by card
That mycin is screened, then by the bacterial strain of growth on the Luria-Bertani containing kanamycin (LB) culture plate, inoculation
To in the LB fluid medium containing kanamycin, 37 DEG C, 250rpm cultivates to exponential phase, then adds isopropylthio
Galactoside (IPTG) to 0.5mM, in 28 DEG C of abduction deliverings 4 hours, finally, is collected by centrifugation antibacterial;
(3) purification of ODC albumen
The antibacterial that will collect in step (2), uses lysate Eddy diffusion, then carries out cell cracking by ultrasonic method, then will
Lysate, at 4 DEG C, 12000 turns/min, after centrifugation, retains supernatant;Finally supernatant is combined using Ni-NTAHis label protein and fill out
Material is combined and purification, obtains ODC albumen, the elution buffer of ODC albumen be 50mM trishydroxymethylaminomethane (Tris)/
HCl, pH 8.0,300mM NaCl, 1mM DTT, 100mM imidazoles (imidazole);
(4) Activity determination of ODC albumen
In EP pipe, add 400uL substrate reactions mixture, the ODC albumen of 50ug, after mixing, EP pipe is placed on 37 DEG C of water-baths
Middle 30min;Add the trichloroacetic acid terminating reaction of 400uL 10%, room temperature is centrifuged 5000rpm, 5min, then takes out on 100uL
Clearly, mix with the NaOH solution of 200uL 4mol/L, add 400uL n-amyl alcohol, be sufficiently mixed, 2000rpm is centrifuged 5min, then
Upper liquid 200uL is transferred in new EP pipe, adds sodium tetraborate mix homogeneously, the addition that 200uL0.1mol/LpH is 8.0
The mixing of 200uL10mmol/L trinitro-benzene-sulfonic acid is abundant, add 400uL DMSO, is sufficiently mixed 1min, 3000rpm is centrifuged
5min;Finally take out upper liquid in 96 orifice plates, detect the light absorption value at 426nm with microplate reader, obtain not enzyme-added OD value;
(5) detection of the inhibitory activity to ODC albumen for the inhibitor
Method according to step (4), after adding 400uL substrate reactions mixture, adds ODC Ornithine decarboxylase immediately
Micromolecular inhibitor, the same step of subsequent operation (4);
ODC suppression ratio is calculated by below equation:
Comparison is poor=plus micromolecular inhibitor matched group mean OD value-do not add micromolecular inhibitor matched group mean OD value, wherein
The inhibitor that matched group adds in step (5) is DFMO inhibitor;
Experiment is poor=plus micromolecular inhibitor experimental group mean OD value-do not add micromolecular inhibitor experimental group group mean OD value;
ODC suppression ratio=[(compareing poor-experiment poor)/comparison is poor] × 100%.
4. method according to claim 3 it is characterised in that:Lysate described in step (3) is 50mM trihydroxy methyl
Aminomethane (Tris)/HCl, pH 8.0,300mM NaCl, 1mM DTT, 1mM PMSF, 5mM imidazoles (imidazole) mixed
Close liquid.
5. the method according to claim 3 it is characterised in that:Substrate reactions mixture in step (4) be
150mMpH is 7.1 phosphate buffer (PBS) middle dissolving 17.57ul beta -mercaptoethanol, 55.84mg 1.5mM EDTA disalt
Sodium, 75nM pyridoxal 5-phosphate (PLP) liquid storage, 2mM dlornithine hydrochloride.
6. method according to claim 3 it is characterised in that:Described ODC Ornithine decarboxylase behaviour source ornithine decarboxylation
Enzyme, inhuman source ODC Ornithine decarboxylase or the putrescine substrate with people source ODC Ornithine decarboxylase and pyridoxal 5-phosphate binding site are highly same
The protein in source.
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CN201410524151.7A CN104739820B (en) | 2014-09-30 | 2014-09-30 | Small molecule inhibitor and application thereof to inhibiting ornithine decarboxylase (ODC) |
PCT/CN2015/091044 WO2016050199A1 (en) | 2014-09-30 | 2015-09-29 | Medicament design pocket of ornithine decarboxylase and application of medicament design pocket |
US15/309,801 US20170314007A1 (en) | 2014-09-30 | 2015-09-29 | Medicament design pocket of ornithine decarboxylase and application of medicament design pocket |
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