Sound-stage Virtual Screening Based on Implicit Ligand Theory

基于隐式配体理论的声场虚拟筛选

• 批准号: 9023233
• 负责人: David Do Le Minh
• 金额: $ 33.74万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023233
• 关键词: Algorithms; Attention; Binding; Binding Proteins; Biological; Biological Assay; Biology; Chemicals; Complex; Computing Methodologies; Dihydrofolate Reductase; Docking; Evaluation; Free Energy; Goals; Human Biology; Individual; Lead; Libraries; Ligand Binding; Ligands; Methods; Molecular; Muramidase; Pharmaceutical Preparations; Phosphotransferases; Physics; Positioning Attribute; Potential Energy; Property; Proteins; Protocols documentation; Receiver Operating Characteristics; Role; Sampling; Scheme; Speed; Staging; Structure; Techniques; Technology; Testing; Virtual Tool; base; computerized tools; cost; design; drug discovery; improved; molecular dynamics; molecular recognition; open source; programs; protein structure; public health relevance; receptor; research study; restraint; screening; simulation; small molecule; small molecule libraries; sound; theories; tool; trend; virtual

 DESCRIPTION (provided by applicant): Virtual screening of chemical libraries is a common starting point for discovering ligands, such as drug leads. The primary tool for virtual screening is molecular docking, which is fast but makes a number of serious approximations about how small molecules interact with proteins. On the other hand, methods based on rigorous statistical physics are much slower and more accurate. We have recently derived a new statistical physics theory for binding that is based on multiple rigid structures of a receptor: implicit ligand theory Computational methods based on this theory have the potential to carefully compromise between the speed of docking and the accuracy of other rigorous methods. Here we develop and assess computational tools to predict (i) whether a molecule will bind to a protein or not, (ii how tightly it binds, and (iii) where it binds. Specifically, we will first test whether binding o a single rigid structure is sufficient to distinguish active from inactive molecules. Second, we wil assess the ability of different molecular simulation methods to generate receptor structures relevant to ligand binding and lead to accurate binding affinity predictions. Third, we will develp algorithms to rank binding poses based on our theory. We anticipate that our methods will be used in the second stage of a virtual screen; after docking millions of compounds, one can use our methods with the top several thousand.

 描述（由适用提供）：化学库的虚拟筛选是发现配体（例如药物铅）的常见起点。虚拟筛选的主要工具是分子对接，它很快，但对小分子如何与蛋白质相互作用进行了许多严重的近似。另一方面，基于严格的统计物理学的方法要慢得多，更准确。我们最近得出了一种基于接收器的多个刚性结构的新统计物理理论：基于该理论的隐式配体理论计算方法具有仔细妥协对接速度和其他严格方法的准确性之间的损害。在这里，我们开发和评估计算工具，以预测（i）分子是否将与蛋白质结合（iii（iii）（iii）的结合程度，以及（iii）它结合的位置。具体地，我们将测试单个刚性结构是否有能力与非活性分子的构图相关，我们将第一次结合o单个刚性结构是否有效。配体结合和准确的结合条件预测。

项目成果

Power transformations improve interpolation of grids for molecular mechanics interaction energies.

• DOI: 10.1002/jcc.25180
• 发表时间: 2018-07-15
• 期刊: Journal of computational chemistry
• 影响因子: 3
• 作者: Minh DDL

Implicit ligand theory for relative binding free energies.

相对结合自由能的隐式配体理论。

• DOI: 10.1063/1.5017136
• 发表时间: 2018
• 期刊: The Journal of chemical physics
• 作者: Nguyen,TrungHai;Minh,DavidDL
• 通讯作者: Minh,DavidDL

Hamiltonian Monte Carlo with Constrained Molecular Dynamics as Gibbs Sampling.

哈密​​顿蒙特卡罗与约束分子动力学作为吉布斯采样。

• DOI: 10.1021/acs.jctc.7b00570
• 发表时间: 2017
• 期刊: Journal of chemical theory and computation
• 影响因子: 5.5
• 作者: Spiridon,Laurentiu;Minh,DavidDL
• 通讯作者: Minh,DavidDL

Absolute Binding Free Energies between T4 Lysozyme and 141 Small Molecules: Calculations Based on Multiple Rigid Receptor Configurations.

• DOI: 10.1021/acs.jctc.6b01183
• 发表时间: 2017-06-13
• 期刊: Journal of chemical theory and computation
• 影响因子: 5.5
• 作者: Xie B;Nguyen TH;Minh DDL
• 通讯作者: Minh DDL

Alchemical Grid Dock (AlGDock) calculations in the D3R Grand Challenge 3 : Binding free energies between flexible ligands and rigid receptors.

• DOI: 10.1007/s10822-018-0143-9
• 发表时间: 2019-01
• 期刊: Journal of computer-aided molecular design
• 影响因子: 3.5
• 作者: Xie B;Minh DDL
• 通讯作者: Minh DDL