CN102270281A - Screening method of anticancer medicament using cyclin-dependent kinases 1 (CDK1) as target - Google Patents
Screening method of anticancer medicament using cyclin-dependent kinases 1 (CDK1) as target Download PDFInfo
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Abstract
The invention discloses a screening method of a novel anticancer medicament using cyclin-dependent kinases 1 (CDK1) as a target. The method comprises the following steps of: 1) acquisition, analysis and processing of a CDK1 protein three-dimensional structure; 2) construction of a small molecule database; 3) establishment of a computer virtual screening system; and 4) bioactive screening. Meanwhile, the invention determines five novel lead compounds with CDK1 inhibiting activity. By the screening method of a CDK1 inhibitor, the novel anticancer lead compounds are quickly, economically and efficiently discovered, and the medicament research and development period is shortened.
Description
Technical field
The present invention relates to utilize the virtual screening technology in conjunction with the active method of carrying out drug screening that detects of external biological, be specifically related to CDK1 is the virtual screening model of inhibitor of target spot and the method for building up of testing in vitro model, and use this method and obtained 5 and have CDK1 and suppress active compounds, can be developed further into and be the new type anticancer medicine.
Background technology
Malignant tumour (claiming cancer again) is the major disease that threatens human health at present, also is one of the highest disease of morbidity rate and fatal rate, and countries in the world have all been dropped into a large amount of manpower and materials and studied.The main dependent cells drug toxicity of but current treatment for cancer clinically, such medicine exist shortcomings such as toxic and side effect is big, poor selectivity, easy generation tolerance, have limited its clinical practice.Therefore, the exploitation low toxicity, new type antineoplastic medicine has become the vital task of current drug research efficiently.
People discover in recent years, and the generation of multiple malignant tumour, development all have substantial connection with the disorder of Cycle Regulation mechanism, so tumour also is considered to a kind of cell cycle disease.After nineteen seventies, three scientists of the U.S. and Britain have successively found cell cycle protein dependent kinase (Cyclin-Dependent Kinases, CDK) and the vital role of cyclin (Cyclins) in cell cycle regulating, thereby obtained calendar year 2001 Nobel Prize in Physiology (Nobel Prize in Physiology or Medicine:Cycling Toward Stockholm, referring to Balter, M., et al.Sci., 2001,294,502).Along with people's cell cycle Study of Mechanism constantly makes substantial progress, particularly disclosed the core status of CDK in cell cycle regulating, the CDK inhibitor has become the research focus of current cancer therapy drug in recent years.
CDK is a class serine/threonine kinase, has short N end (beta sheet) and long C end (alpha-helix), and its ATP binding pocket is between N end and C end.CDK played a role in each stage of cell cycle, impelled cell to carry out orderly propagation (Ubiquitin ligases:cell-cycle control and cancer, referring to Nakayama, K.I., etal.Nat.Rev.Cancer, 2006,6,369).Different with other kinases is, CDK must form the effect of dimer complex competence exertion with corresponding C yclins, and expresses and degraded by the periodicity of Cyclins, promote the cell cycle each the time the carrying out in order of phase, cause cell growth, propagation.In addition, CDK also can combine with the CDK inhibiting factor, the blocking-up cell division.Confirmed to have 13 CDK members (CDK1～13) in the human body, corresponding with it have 12 Cyclins (A～L).Think that at present what play regulating action in the cell cycle mainly is CDK1～4,6 and 7, the effect (see figure 1) that the polymkeric substance of these CDK members and Cyclins is brought into play in cell cycle in each stage.
(Cyclin-Dependent Kinases Inhibitor's cell cycle protein dependent kinase inhibitor CDKI) plays a role by the ATP-binding domain territory that combines CDK with ATP competitiveness, can effectively stop cell proliferation or promote Apoptosis.The research of CDK inhibitor has the history of more than ten years, and existing at present a plurality of CDK inhibitor have entered the clinical research stage.
No matter traditional drug screening method is random screening or high flux screening, all exists the shortcoming that cost is huge, success ratio is low.In this year, along with the development of computer modeling technique and the proposition of various basic algorithms, the utilization analogue technique is carried out the medicine virtual screening and is become a reality.Therefore, set up a trocar to antitumor target spot CDK efficient, the machine-processed research and development for new type antineoplastic medicine of rapid screening are significant.
Summary of the invention
General introduction
At the deficiencies in the prior art, the invention discloses a kind of is the screening technique of the cancer therapy drug of target spot with CDK1, its purpose be to set up a kind of with CDK1 be target spot the new type anticancer medicine screening technique and use this method and filter out and have CDK1 and suppress active lead compound, to remedy the deficiencies in the prior art.
Of the present invention being contemplated that: at first use computer modeling technique, set up the virtual screening model of CDK1 inhibitor; By setting up the external activity screening model of CDK1 inhibitor, the virtual screening positive compound is carried out postsearch screening again, obtain that finally CDK1 is had the compound that suppresses active.
Describe in detail
Technical scheme of the present invention, a kind of is the screening technique of the cancer therapy drug of target spot with CDK1, its step is as follows:
1) the CDK1 protein three-dimensional structure obtains, analyzes and handle;
2) structure of micromolecule database;
3) foundation of computer virtual screening system;
4) bioactivity screening;
Obtain 5 altogether by the two-wheeled screening and had the compound that CDK1 suppresses activity;
This compound has following feature:
Compound-1
English name: N-(2,4-dichlorophenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide compound structure:
Compound-2
English name: 4-(2-((5-phenylfuran-2-yl) methylamino) ethyl) benzenesulfonamide compound structure:
Compound-3
English name: 4-methyl-N-(2-(3,4,5-trimethyl-1H-pyrazol-1-yl) propyl) benzenesulfonamide compound structure:
Compound-4
English name: 5-(2-aminopropyl)-3-methyl-1,4-diphenyl-4,5-dihydropyrrolo[3,4-c] pyrazol-6 (1H)-one compound structure:
Compound-5
English name:
1-(2-oxo-2-(3-(thiophen-2-yl)-3,3a, 4,5-tetrahydro-2H-benzo[g] indazol-2-yl) ethyl) the piperidinium compound structure:
The obtaining, analyze and handle of described step 1) CDK1 protein three-dimensional structure:
Adopt build the CDK1 three-dimensional structure of acquisition early stage, and use SiteID (SYBYL7.3, Tripos Inc.) to determine avtive spot by the homology mould.
Described step 2) structure of micromolecule database:
Small molecule structure obtains from the ZINC database, and the quasi-medicated property screening relies on Li Binsiji five rules; Small molecule structure by screening utilizes Concord (SYBYL7.3, Tripos Inc.) to carry out the three-dimensional structure conversion, and micromolecule is added Gasteiger-H ü ckel electric charge.
The foundation of described step 3) computer virtual screening system:
For speed that improves the search of virtual screening model conformation and the credibility of giving a mark and sorting, said method: step 3) adopts the molecular docking software Gold (Discovery Studio) based on genetic algorithm, use CScore (SYBYL simultaneously, Tripos Inc.) the marking result is carried out consistency analysis, promptly use five kinds of scoring functions such as Chem_Score, D_Score, PMF_Score, Total_Score, D_Score that the virtual screening result is carried out secondary marking, and carry out comprehensive evaluation.
Accelerate breakneck acceleration, said method: step 2 simultaneously in order to improve success ratio) can place step 1) before any one step between the step 4).
Select compound according to the virtual screening result and carry out biological activity test, the final discovery has the lead compound that CDK1 suppresses activity.
The invention has the beneficial effects as follows:
The present invention can obtain to have CDK1 at short notice and suppress active compound by setting up virtual screening model and external activity test model, reduces the compound quantity of carrying out active testing simultaneously greatly, has effectively saved cost.Final 5 compounds that obtain all have certain CDK1 and suppress active, and the potentiality that are developed further into to the new type antineoplastic medicine molecule are arranged.
Description of drawings
Fig. 1 is the cell cycle phase of portion C DK-Cycylins polymkeric substance cytosis;
Fig. 2 is the primary sequence of CDK1;
Fig. 3 builds the CDK1 tertiary structure that obtains for the homology mould;
Fig. 4 is the avtive spot (with the part that outline line marks, representative inhibitor spherical model shows) of CDK1 and inhibitor effect.
Embodiment
Below in conjunction with Figure of description and embodiment the present invention is done to explain, but be not limited thereto.
A kind of is the screening technique of the cancer therapy drug of target spot with CDK1, and step is as follows:
1) three-dimensional crystalline structure of obtaining of CDK1 protein three-dimensional structure: CDK1 does not appear in the newspapers, in order better such medicine to be studied, we select three-dimensional structure (the Homology modeling of the CDK1 that we make up by the homology mould mode of building early stage, molecular dynamic simulation and docking studies of cyclin dependent kinase 1, referring to Lei, Zhang., et al.J.Mol.Model., 2011,17,219); The acquisition of this structure is the sequence (see figure 2) from CDK1, is template with the CDK2 crystal structures such as (PDB code:3EZR) with higher homology, utilizes ORCHESTAR program (SYBYL7.3, Tripos Inc.) to finish the structure (see figure 3);
Use SiteID (SYBYL7.3, Tripos Inc.) to determine the binding site (see figure 4) of CDK1 and positive drug.
2) structure of micromolecule database: the micromolecule database in this example is from the ZINC storehouse, and being one is the free micromolecule database that Shoichet seminar sets up and safeguards by University of California's pharmaceutical chemistry.The present version of ZINC is ZINC8, and inclusion compound quantity is very huge, has to surpass 1,300 ten thousand compounds.In this example, we have selected 1,100,000 compounds in ASDI, Asinex and the ChemBridge lamp database, and (molecular weight of compound is less than 500 dalton by Li Binsiji five rules; The quantity of the hydrogen-bond donor in the compound structure is no more than 5; The quantity of hydrogen bond receptor is no more than 10 in the compound; The logarithm value logP of the lipid of compound is between-2 to 5; The quantity of rotatable key is no more than 10 in the compound) be carried out to property of medicine screening, finally obtain about 800,000 compounds and form the micromolecular compound storehouse; Use Concord (SYBYL7.3, Tripos Inc.) that the molecule in the compound library is converted to 3-D solid structure, and add Gasteiger-H ü ckel electric charge.
3) foundation of computer virtual screening system:
Adopt molecular docking software Gold to carry out the foundation of computer virtual screening system in conjunction with CScore, key step is as follows:
A. read the CDK1 three-dimensional structure that the homology modeling obtains, hydrogenation adds electric charge;
B. according to binding site analysis result in 1., select coordinate x=9, y=13, z=-6 are the center, around this center
Zone Full in the 10 dust scopes is as the molecular docking zone;
C. with chemscore_kinase template; Select treated micromolecular compound storehouse;
D. select the chemscore scoring functions, the Parameter File after the optimization thes contents are as follows:
#ChemScore?coefficients：
ZERO_COEFFICIENT -5.48
HBOND_COEFFICIENT -3.34
METAL_COEFFICIENT -6.03
LIPO_COEFFICIENT -0.117
ROT_COEFFICIENT 2.56
INTRA_COEFFICIENT 1.00
LINK_BEND_COEFFICIENT 0.25
#Hydrogen-bond?term：
HBOND_FUNCTION?CHEMSCORE_DOCKING
R_IDEAL 1.85
DELTA_R_IDEAL 0.25
DELTA_R_MAX 0.65
HBOND_R_SIGMA 0.1
ALPHA_IDEAL 180.0
DELTA_ALPHA_IDEAL 30.0
DELTA_ALPHA_MAX 80.0
HBOND_ALPHA_SIGMA 10.0
BETA_IDEAL 180.0
DELTA_BETA_IDEAL 70.0
DELTA_BETA_MAX 80.0
HBOND_BETA_SIGMA 10.0
#Metal?term：
METAL_R1 2.6
METAL_R2 3.0
METAL_R_SIGMA0.1
#Lipophilic?term：
LIPO_R1 4.1
LIPO_R2 7.1
LIPO_R_SIGMA0.1
#Clash?terms：
CLASH_FUNCTION?CHEMSCORE_DOCKING
CLASH_RADIUS_GENERAL 3.10
CLASH_RADIUS_SULPHUR 3.35
CLASH_RADIUS_HBOND 1.60
CLASH_RADIUS_METAL 1.38
CLASH_RADIUS_SIGMA 0.1
#Torsion?terms：
SP3_SP3_BOND?0.187503.03.1515926
SP3_SP2_BOND?0.093756.00.0000000
SP2_SP2_BOND?0.187502.00.0000000
UNKNOWN_BOND?0.000000.00.0000000
#Scaling：
HBOND_SCALING?1
HBOND_SCALING_SAMPLES?1
HBOND_SCALING_END?75.0
DELTA_R_MAX_START?1.15
DELTA_ALPHA_MAX_START?110.0
#Maps：
GRID_SPACING?0.2
#Io：
CLASH_MAP_FILENAME?chemscore_clash_map.grd
LIPO_MAP_FILENAME?chemscore_lipo_map.grd
LOAD_MAPS?0
SAVE_MAPS?0
E. select genetic algorithm parameter, as follows:
Population?size：100
Selection?pressure：1.1
Number?of?operations：100000
Number?of?islands：5
Niche?size：2
Crossover?frequency：95
Mutation?frequency：95
Migration?frequency：10
F. click Run GOLD molecular docking is carried out in the micromolecular compound storehouse;
G. open SYBYL7.3, newly-built molecule list, key in as order startup CScore at command bar:
table?attribute?create?ORIGIN?string
table?attribute?set?ORIGIN?DOCKING
Then, import the butt joint result of step f., can use five kinds of scoring functions Chem_Score, D_Score, PMF_Score, Total_Score, D_Score that the result is carried out the consistance evaluation;
So far, the virtual screening model is set up, if need carry out virtual screening to other micromolecule databases, only needs to select new micromolecule database in step c.
4) foundation of external biological screening active ingredients model
CDK1/CycB Kinase Assay Kit kit is available from Cell Signaling Technology (#7519), comprise in the kit enzyme CDK1/CycB Kinase (recombinant, human), substrate Rb (Ser780) Biotinylated Peptide, antibody Phospho-Rb (Ser780) Antibody, ATP, Kinase Buffer (10X).
Specific embodiments reference reagent box instructions or (Liu Ning, the design of chalcones cell cycle protein dependent kinase inhibitor, synthetic and antitumor activity research [D], Shandong University, 2010).
By the active testing of step 4) to the virtual screening positive compound, found that 5 have the compound that CDK1 suppresses activity, this compound has following feature (wherein the CDK1 inhibiting rate records at 50 μ m, the positive compound of flavopiridol): compound-1
CDK1 inhibiting rate: 25.19%
English name: N-(2,4-dichlorophenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide compound structure:
Compound-2
CDK1 inhibiting rate: 23.96%
English name: 4-(2-((5-phenylfuran-2-yl) methylamino) ethyl) benzenesulfonamide compound structure:
Compound-3
CDK1 inhibiting rate: 20.12%
English name: 4-methyl-N-(2-(3,4,5-trimethyl-1H-pyrazol-1-yl) propyl) benzenesulfonamide compound structure:
Compound-4
CDK1 inhibiting rate: 10.10%
English name: 5-(2-aminopropyl)-3-methyl-1,4-diphenyl-4,5-dihydropyrrolo[3,4-c] pyrazol-6 (1H)-one compound structure:
Compound-5
CDK1 inhibiting rate: 10.52%
English name:
1-(2-oxo-2-(3-(thiophen-2-yl)-3,3a, 4,5-tetrahydro-2H-benzo[g] indazol-2-yl) ethyl) the piperidinium compound structure:
Claims (5)
1. one kind is the screening technique of the cancer therapy drug of target spot with CDK1, and its step is as follows:
1) the CDK1 protein three-dimensional structure obtains, analyzes and handle;
2) structure of micromolecule database;
3) foundation of computer virtual screening system;
4) bioactivity screening;
Obtain 5 altogether by the two-wheeled screening and had the compound that CDK1 suppresses activity;
This compound has following feature:
Compound-1
English name: N-(2,4-dichlorophenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl) methyl) furan-2-carboxamide compound structure:
Compound-2
English name: 4-(2-((5-phenylfuran-2-yl) methylamino) ethyl) benzenesulfonamide compound structure:
Compound-3
English name: 4-methyl-N-(2-(3,4,5-trimethyl-1H-pyrazol-1-yl) propyl) benzenesulfonamide compound structure:
Compound-4
English name: 5-(2-aminopropyl)-3-methyl-1,4-diphenyl-4,5-dihydropyrrolo[3,4-c] pyrazol-6 (1H)-one compound structure:
Compound-5
English name:
1-(2-oxo-2-(3-(thiophen-2-yl)-3,3a, 4,5-tetrahydro-2H-benzo[g] indazol-2-yl) ethyl) the piperidinium compound structure:
2. as claimed in claim 1 a kind of be the screening technique of the cancer therapy drug of target spot with CDK1, it is characterized in that the obtaining, analyze and handle of described step 1) CDK1 protein three-dimensional structure:
Adopt build the CDK1 three-dimensional structure of acquisition early stage, and use SiteID (SYBYL7.3, Tripos Inc.) to determine avtive spot by the homology mould.
3. as claimed in claim 1 a kind of be the screening technique of the cancer therapy drug of target spot with CDK1, it is characterized in that described step 2) structure of micromolecule database:
Small molecule structure obtains from the ZINC database, and the quasi-medicated property screening relies on Li Binsiji five rules; Small molecule structure by screening utilizes Concord (SYBYL7.3, Tripos Inc.) to carry out the three-dimensional structure conversion, and micromolecule is added Gasteiger-H ü ckel electric charge.
4. as claimed in claim 1 a kind of be the screening technique of the cancer therapy drug of target spot with CDK1, it is characterized in that the foundation of described step 3) computer virtual screening system:
For speed that improves the search of virtual screening model conformation and the credibility of giving a mark and sorting, said method: step 3) adopts the molecular docking software Gold (Discovery Studio) based on genetic algorithm, use CScore (SYBYL simultaneously, Tripos Inc.) the marking result is carried out consistency analysis, promptly use five kinds of scoring functions such as Chem Score, D Score, PMF Score, Total Score, D Score that the virtual screening result is carried out secondary marking, and carry out comprehensive evaluation.
5. as claimed in claim 1 a kind of be the screening technique of the cancer therapy drug of target spot with CDK1, it is characterized in that described step 2) place step 1) before any one step between the step 4).
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Application publication date: 20111207 |