Accounting for Water Structure and Thermodynamics in Computer-Aided Drug Design

计算机辅助药物设计中的水结构和热力学考虑

• 批准号: 9060952
• 负责人: MICHAEL K. GILSON
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060952
• 关键词: Accounting; Amber; Area; Binding; Binding Proteins; Binding Sites; Complex; Computer Assisted; Computer software; Computing Methodologies; Coupled; Data; Data Set; Disease; Docking; Drug Design; Educational workshop; Entropy; Environment; Equation; Free Energy; Goals; Health; Hydration status; Hydrogen Bonding; Imagery; Ligands; Methods; Modeling; Molecular; Nature; Pattern; Pharmaceutical Preparations; Process; Property; Proteins; Role; Scientist; Scoring Method; Site; Software Tools; Solid; Solvents; Speed; Structure; Surface; Techniques; Thermodynamics; Time; Water; Work; advanced simulation; base; computerized tools; density; design; drug discovery; improved; insight; molecular dynamics; novel; open source; simulation; standard care; theories; tool

DESCRIPTION (provided by applicant): This project aims to develop new computational tools that will speed structure-based drug-discovery by providing a detailed analysis of hydration structure and thermodynamics of water in targeted protein binding pockets. The fundamental concept is to discretize the equations of inhomogeneous solvation theory (IST), up to second order, onto 3D grids of energy and entropy in a targeted binding site. These grids will be populated by molecular dynamics (MD) simulations with explicit solvent. The resulting treatment of solvation, termed GIST, will be characterized through comparisons with experimental data and rigorous thermodynamic integration free energy calculations for protein binding pockets. The GIST method will be incorporated into visualization tools to highlight binding site regions where it is particularly favorable or unfavorable to displace solvent, in order to speed ligand design and evaluate the "druggability" of protein binding pockets. It will also be integrated into fast new functions for ligand docking and scoring, for which promising preliminary results are provided in this proposal. Finally, in order to maximize scientific and health impact, the software will be packaged, documented and disseminated as part of the freely available, widely used and open source AMBER Tools software suite.

描述（由申请人提供）：该项目旨在开发新的计算工具，通过对目标蛋白质结合袋中水的水合结构和热力学进行详细分析，加速基于结构的药物发现。基本概念是将非齐次溶剂化理论 (IST) 方程离散化到二阶，并离散化到目标结合位点的能量和熵的 3D 网格上。这些网格将由具有显式溶剂的分子动力学 (MD) 模拟填充。由此产生的溶剂化处理称为 GIST，将通过与实验数据的比较和蛋白质结合袋的严格热力学积分自由能计算来表征。 GIST 方法将被纳入可视化工具中，以突出显示特别有利或不利于置换溶剂的结合位点区域，以加快配体设计并评估蛋白质结合袋的“成药性”。它还将被集成到用于配体对接和评分的快速新功能中，本提案为此提供了有希望的初步结果。最后，为了最大限度地发挥科学和健康影响，该软件 将作为免费提供、广泛使用的开源 AMBER Tools 软件套件的一部分进行打包、记录和传播。