CN104598772A - Construction method for gout drug effect enzyme target model - Google Patents
Construction method for gout drug effect enzyme target model Download PDFInfo
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- CN104598772A CN104598772A CN201410824704.0A CN201410824704A CN104598772A CN 104598772 A CN104598772 A CN 104598772A CN 201410824704 A CN201410824704 A CN 201410824704A CN 104598772 A CN104598772 A CN 104598772A
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Abstract
The invention relates to a construction method for a gout drug effect enzyme target model. The construction method includes the steps that molecular docking software is used for carrying out preliminary screening on a database and carrying out in-vitro activity experiments and spectroscopic analysis, and the molecular docking software is used again for simulating 1000-2000 times to set up the enzyme target PDB3 model. According to the construction method, as the Discovery studio molecular docking software is adopted for base comparison, the drug range of the activity experiments is greatly reduced, a great deal of cost is saved for researching and developing new drugs, and the researching and developing cycle for a gout key enzyme inhibitor is shortened; after the in-vitro enzyme activity experiments and in-vitro spectroscopic experiments are completed, the molecular docking software is used again for further screening the database and comparing the database with in-vitro experiment data, so that the researching and developing speed is increased, and the researching and developing cost is saved; as the enzyme target PDB3 model is set up, the key function target spot of xanthine oxidase is determined, the researching and developing cycle for gout diseases is greatly shortened, the directionality and purposiveness of research and development are definite, and the in-vitro and in-vivo effects are better.
Description
Technical field
The present invention relates to a kind of drug effect target model, the enzyme target amino acid sequence particularly relating to a kind of construction method for the treatment of the enzyme target model of the enzyme level medicine of gout He utilize the method to obtain.
Background technology
Along with people of the world's growth in the living standard, the incidence of disease of hyperuricemia and gout increases year by year, and the incidence of disease of its elderly and the male sex is higher.The current patient with gout of China is about more than 1,200 ten thousand, and hyperuricemia person about has 1.2 hundred million.Hyperuricemia can be divided into primary and Secondary cases, and the former is mainly caused by kidney underexcretion and uric acid generate too much, and the latter is relevant with relevant disease.And the pathogenesis of gout has several factors: inherent cause, environmental factor, mental element, race, life style, eating habit etc.In body, the generative process of uric acid is also along with the generation of peroxide radical, by suppressing the activity of xanthine key enzyme-xanthine oxidase (XO), the generation of uric acid can be suppressed, and adjust the balance of uric acid in human metabolism, therefore XO inhibitor can well control to alleviate hyperuricemia and gout root.Xanthine oxidase one has 1060 amino acid residues, and wherein moiety (site) can directly be combined with medicine or indirectly produce intermolecular interaction, and these sites determine the inhibiting effect of medicine to xanthine oxidase.
At present clinically for suppressing the inhibitor mainly allopurinol (Allopur-inol) of XO activity, it is a kind of competitive purine analogue inhibitor, also be hypoxanthic isomeride, it can with the Mo of enzyme active center (IV) strong bonded, make Mo (IV) that Mo (VI) can not be changed easily into.And then inhibit the generation of uric acid.But allopurinol can cause the toxic and side effects such as allergy, hepar damnification and bone marrow suppression, therefore limits its clinical practice to a certain extent.Therefore, study the XO inhibitor tool that new safety has no side effect to be of great significance, but because traditional XO suppresses the R & D Cost of new drug development high, the research and development screening cycle is long especially, how to set up an expense low, respond well medicine enzyme target model and accurate enzyme target amino acid sequence, become the focus of current research, this model not only can bring good economic benefit, and significantly can shorten the R&D cycle of gout proteases inhibitors medicine, thus bring glad tidings to vast patient with gout.
Summary of the invention
For traditional new drug development cycle is long, R & D Cost is high, control effect and mechanism is indefinite and targeting enzymes suppresses problem, the construction method that the invention provides a kind of enzyme inhibitor targeting model and the enzyme target amino acid sequences utilizing the method to obtain such as site sequence the unknown.
From molecular model storehouse (http://www.rcsb.org/pdb), find corresponding XO model (PDB ID 3ETR), and from senior chemical Development Co., Ltd of U.S. database (ACD), drug data report database (MDDR), Holland's drug data base (SPECS), corresponding medicine is screened in the databases such as CNPD (CNPD), adopt the brand-new molecular simulation software of Discovery Studio, to all can with minimum energy, the medicine combined with xanthine oxidase of the highest connecting times carries out preliminary data screening, and set up corresponding PDB
1file, by all can in conjunction with the PDB of material
2piece file mergence, determines to set up clear and definite binding sequence XO binding site model-enzyme target model, then chooses corresponding medicine, carries out external activity experiment, Structural Identification, the simulation of target binding site, utilize the suppression dosage and the parameters revision such as binding constant, binding site number PDB of testing and obtaining
2, obtain PDB
3(enzyme target model), and clear and definite enzyme target amino acid sequence.Change tradition purposelessly, poor efficiency screening operation, substantially reduce the research and development time of gout relevant enzyme inhibitor class and significantly reduce the expense of research and development, to gout class medicament research and development, enterprise brings huge economic benefit.
In order to solve the problems of the technologies described above, the present invention is solved by the following technical programs:
L () finds corresponding XO model PDB ID 3ETR from the http://www.rcsb.org/pdb of molecular model storehouse, and corresponding medicine is screened from ACD database, MDDR database, SPECS database, CNPD database database, adopt the brand-new molecular simulation software of Discovery Studio, can carry out preliminary data screening with the medicine combined with xanthine oxidase of minimum energy, high connecting times to all, screening number of times is the PDB obtaining several medicines and XO combination for 100 to 200 times
1file;
(2) by all PDB
1meet following condition: A, be-10 to-5kJ/mol in conjunction with energy; B and the lowest energy conformation accounts for 10 to 50% of the conformation of all simulations; The conformation meeting above condition is generated PDB
1file, and by all several PDB obtained
1conformation merges generation primary election target position model PDB
2; And will PDB be met
2active substance
,carry out external inhibitory enzyme activity experiment;
(3) by the xanthine oxidase IC of external suppression medicine
50the suppression medicine of < 10mmol/L, carries out spectroscopy experiment, determines its bond type, binding constant, binding site number;
(4) to meeting (3) condition medicine, carry out fluorescence thermodynamic analysis, analyze its be combined with each other effect in conjunction with energy; Again carry out Discovery Studio molecular simulation to above medicine, number realization is 1000 to 2000 times, the binding site number calculated in conjunction with (3), (4), combines the correction carrying out model;
(5) the molecular simulation binding site after correcting according to (4), carries out conclusion and gathers, find out the amino acid sequence of homology.And set up the targeting site model PDB of gout key enzyme-xanthine oxidase inhibitor
3; Find that in the amino acid of xanthine oxidase 800 to 1100 position, partial amino-acid is the key enzyme action target spot of xanthine oxidase through 35000 kinds of general chemical material comparisons.
Accompanying drawing explanation
Fig. 1 is the construction step figure of gout drug effect enzyme target model of the present invention.
Embodiment
Below in conjunction with accompanying drawing and embodiment, the present invention is described in further detail:
Embodiment one
From molecular model storehouse (http://www.rcsb.org/pdb), find corresponding XO model (PDB ID 3ETR), and corresponding medicine is screened from ACD database, MDDR database, SPECS database, CNPD database database, adopt the brand-new molecular simulation software of Discovery Studio, can carry out preliminary data screening with the medicine combined with xanthine oxidase of minimum energy, high connecting times to all, screening number of times is the PDB obtaining several medicines and XO combination for 200 to 400 times
1.
(2) and by all PDB
1meet following condition: 1, in conjunction with energy-10 to-6kJ/mol; 2 and the lowest energy conformation accounts for 20% to 40% of the conformation of all simulations.The conformation meeting above condition is generated PDB
1file, and by all several PDB obtained
1conformation merges generation primary election target position model PDB
2.And will PDB be met
2active substance
,carry out external inhibitory enzyme activity experiment.
(3) by the xanthine oxidase IC of external suppression medicine
50the suppression medicine of < 10mmol/L, carries out spectroscopy experiment, determines its bond type, binding constant, binding site number.
(4) to meeting (3) condition medicine, carry out fluorescence thermodynamic analysis, analyze its be combined with each other effect in conjunction with energy.Again carry out Discovery Studio molecular simulation to above medicine, number realization is 1000-2000 time, the binding site number calculated in conjunction with (3), (4), combines the correction carrying out model.
(5) the molecular simulation binding site after correcting according to (4), carries out conclusion and gathers, find out the amino acid sequence of homology.And set up gout key enzyme-xanthine oxidase inhibitor, targeting site model (PDB
3).Find that in the amino acid of xanthine oxidase 800-1100 position, partial amino-acid is the key enzyme action target spot of xanthine oxidase through 35000 kinds of general chemical material comparisons.
Embodiment two
L () is from molecular model storehouse (http://www.rcsb.org/pdb), find corresponding XO model (PDB ID 3ETR), and corresponding medicine is screened from ACD database, MDDR database, SPECS database, CNPD database database, adopt the brand-new molecular simulation software of Discovery Studio, can carry out preliminary data screening with the medicine combined with xanthine oxidase of minimum energy, high connecting times to all, screening number of times is the PDB obtaining several medicines and XO combination for 200-400 time
1.
(2) and by all PDB
1meet following condition: 1, in conjunction with energy-10 to-3kJ/mol; 2 and the lowest energy conformation accounts for 20% to 30% of the conformation of all simulations.The conformation meeting above condition is generated PDB
1file, and by all several PDB obtained
1conformation merges generation primary election target position model PDB
2.And will PDB be met
2active substance
,carry out external inhibitory enzyme activity experiment.
(3) by the xanthine oxidase IC of external suppression medicine
50the suppression medicine of < 10mmol/L, carries out spectroscopy experiment, determines its bond type, binding constant, binding site number.
(4) to meeting (3) condition medicine, carry out fluorescence thermodynamic analysis, analyze its be combined with each other effect in conjunction with energy.Again carry out Discovery Studio molecular simulation to above medicine, number realization is 2000-3000 time, the binding site number calculated in conjunction with (3), (4), combines the correction carrying out model.
(5) the molecular simulation binding site after correcting according to (4), carries out conclusion and gathers, find out the amino acid sequence of homology.And set up gout key enzyme-xanthine oxidase inhibitor, targeting site model (PDB
3).Entered 35000 kinds of general chemical material comparisons and found that in the amino acid of xanthine oxidase 800-1100 position, partial amino-acid was the key enzyme action target spot of xanthine oxidase.
Embodiment three
L () is from molecular model storehouse (http://www.rcsb.org/pdb), find corresponding XO model (PDB ID 3ETR), and corresponding medicine is screened from ACD database, MDDR database, SPECS database, CNPD database database, adopt the brand-new molecular simulation software of Discovery Studio, can carry out preliminary data screening with the medicine combined with xanthine oxidase of minimum energy, high connecting times to all, screening number of times is the PDB obtaining several medicines and XO combination for 200-400 time
1.
(2) and by all PDB
1meet following condition: 1, in conjunction with energy lower than-8 to-2kJ/mol; 2 and the lowest energy conformation accounts for 10% to 20% of the conformation of all simulations.The conformation meeting above condition is generated PDB
1file, and by all several PDB obtained
1conformation merges generation primary election target position model PDB
2.And will PDB be met
2active substance
,carry out external inhibitory enzyme activity experiment.
(3) by the xanthine oxidase IC of external suppression medicine
50the suppression medicine of < 10mmol/L, carries out spectroscopy experiment, determines its bond type, binding constant, binding site number.
(4) to meeting (3) condition medicine, carry out fluorescence thermodynamic analysis, analyze its be combined with each other effect in conjunction with energy.Again carry out Discovery Studio molecular simulation to above medicine, number realization is 2000 to 3000 times, the binding site number calculated in conjunction with (3), (4), combines the correction carrying out model.
(5) the molecular simulation binding site after correcting according to (4), carries out conclusion and gathers, find out the amino acid sequence of homology.And set up gout key enzyme-xanthine oxidase inhibitor, targeting site model (PDB
3).Find that in the amino acid of xanthine oxidase 800 to 1100 position, partial amino-acid is the key enzyme action target spot of xanthine oxidase through 35000 kinds of general chemical material comparisons.
Claims (2)
1. a construction method for gout drug effect enzyme target model, is characterized in that:
L () finds corresponding XO model PDB ID 3ETR from the http://www.rcsb.org/pdb of molecular model storehouse, and corresponding medicine is screened from ACD database, MDDR database, SPECS database, CNPD database database, adopt the brand-new molecular simulation software of Discovery Studio, can carry out preliminary data screening with the medicine combined with xanthine oxidase of minimum energy, high connecting times to all, screening number of times is the PDB obtaining several medicines and XO combination for 100 to 200 times
1file;
(2) by all PDB
1meet following condition: A, be-10 to-5kJ/mol in conjunction with energy; B and the lowest energy conformation accounts for 10 to 50% of the conformation of all simulations; The conformation meeting above condition is generated PDB
1file, and by all several PDB obtained
1conformation merges generation primary election target position model PDB
2; And will PDB be met
2active substance
,carry out external inhibitory enzyme activity experiment;
(3) by the xanthine oxidase IC of external suppression medicine
50the suppression medicine of < 10mmol/L, carries out spectroscopy experiment, determines its bond type, binding constant, binding site number;
(4) to meeting step (3) condition medicine, carry out fluorescence thermodynamic analysis, analyze its be combined with each other effect in conjunction with energy; Again carry out Discovery Studio molecular simulation to above medicine, number realization is 1000 to 2000 times, and the binding site number that integrating step (3), step (4) calculate, combination can carry out the correction of model;
(5) the molecular simulation binding site after correcting according to step (4), carries out conclusion and gathers, find out the amino acid sequence of homology; And set up the targeting site model PDB of gout key enzyme-xanthine oxidase inhibitor
3; Find that in the amino acid of xanthine oxidase 800 to 1100 position, partial amino-acid is the key enzyme action target spot of xanthine oxidase through 35000 kinds of general chemical material comparisons.
2. the construction method of a kind of gout drug effect enzyme target model according to claim 1, it is characterized in that: utilize this model to draw enzyme target amino acid sequence, Ala846, Val850, Phe852, Leu875, Phe885, Vla912, Ser931, Vla1014, Ala1020, Ala1022 are the key enzyme action target spot of xanthine oxidase.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112748209A (en) * | 2020-12-22 | 2021-05-04 | 浙江工业大学 | Anti-gout drug screening method based on modified fiber enrichment |
| CN113140266A (en) * | 2021-05-20 | 2021-07-20 | 东北农业大学 | Screening method of xanthine oxidase inhibitor for reducing uric acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112748209A (en) * | 2020-12-22 | 2021-05-04 | 浙江工业大学 | Anti-gout drug screening method based on modified fiber enrichment |
| CN113140266A (en) * | 2021-05-20 | 2021-07-20 | 东北农业大学 | Screening method of xanthine oxidase inhibitor for reducing uric acid |
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Application publication date: 20150506 |