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Computer-Aided Drug Design Targeting Protein Phosphorylation

Computer-Aided Drug Design Targeting Protein Phosphorylation
针对蛋白质磷酸化的计算机辅助药物设计
批准号:
10436417
负责人:
Chung F. Wong
金额:
$46.95万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
未结题
起止时间:
2019-02-01 至 2025-03-31

项目摘要

项目成果

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中文摘要
翻译
作为长期目标的一部分,开发和应用计算方法来帮助药物靶向设计
英文摘要
As part of the long-term goal to develop and apply computational methods to aid the design of drugs targeting protein kinases and related proteins, this research focuses on the development and application of the ensemble docking method, and on the study of drug-binding kinetics. Protein kinases continue to be the main targets for drug discovery in this research. The approval of about 60 inhibitors of protein kinases as drugs, mainly for treating cancer, has demonstrated protein kinases as important drug targets. As over 500 protein kinases are present in human and many mutants are driving diseases, many more drugs can be developed by targeting protein kinases. Specific Aim 1 continues to develop and apply the ensemble docking method to drug discovery. Aim 1a tests the hypothesis that scores, or their derivatives, from ensemble docking could predict whether lung cancer patients carrying disease-driving mutants of protein kinases are responsive to approved drugs. Aim 1b continues to validate the use of machine learning to improving ensemble docking. The validation will include all the proteins in the Directory of Useful Decoys-Enhanced developed for evaluating the performance of docking methods. Ensemble docking/machine learning models for these proteins will be made available to other scientists through the web server EDock-ML. Scientists can submit a compound to EDock-ML and receive the probability that the compound to be active. Aim 1c identifies new drug leads for the protein kinase c-MET with the aid of EDock-ML. Specific Aim 2 continues to test a combination of simulation methods for rapidly identifying compounds with therapeutically useful drug-binding kinetics, using more experimental data that are becoming available. It uses steered molecular dynamics (SMD) simulation for fast initial screening of chemical libraries, followed by evaluating the most promising subset by expensive but more rigorous methods, including the umbrella sampling technique, the Markov State Model, and the milestoning method. As it is still challenging to calculate absolute dissociation/association rate from molecular simulations, using several methods employing different approximations will help to draw robust and unbiased conclusions. After validation, the trajectories from the simulation will be used to decipher the molecular mechanisms of drug dissociation from protein kinases, including the examination of the generality of a two-step dissociation mechanism that has already been identified. Understanding the molecular mechanisms can give hint on the design of drugs with therapeutically useful drug-binding kinetics. The projects are designed to be performed by undergraduates. Senior scientists will work alongside the students often so that projects with higher impact can be included.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
DOI: 10.3390/life11020074
发表时间: 2021-01-20
期刊: Life (Basel, Switzerland)
影响因子: --
作者: [Spiriti J, Wong CF]
通讯作者: Wong CF
DOI: 10.1002/prot.25899
发表时间: 2020-10
期刊: Proteins
影响因子: 2.9
作者: [Chandak T, Mayginnes JP, Mayes H, Wong CF]
通讯作者: Wong CF
Simulation of ligand dissociation kinetics from the protein kinase PYK2.
从蛋白激酶Pyk2中的配体解离动力学的模拟。
DOI: 10.1002/jcc.26991
发表时间: 2022-10-30
期刊: Journal of computational chemistry
影响因子: 3
作者: [Spiriti J, Noé F, Wong CF]
通讯作者: Wong CF
MODELING OF CONTRIBUTION OF PARTIAL CHARGES TO PROTEIN-LIGAND
CONTINUUM ELECTROSTATISTICS THEORY
CONTINUUM ELECTROSTATISTICS THEORY
Anti-plague agents targeting YopH of Yersinia Pestis
  • 批准号:
    7502069
  • 项目类别:
  • 资助金额:
    $18.52万
  • 财政年份:
    2007
  • 负责人:
    Chung F. Wong
  • 依托单位:
海外基金