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: 8727620
• 负责人: MICHAEL K. GILSON
• 金额: $ 32.63万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727620
• 关键词: Accounting; Amber; Area; Binding; 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; Protein Binding; Proteins; Relative (related person); 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; public health relevance; 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，通过对靶向蛋白质结合口袋中水的水合结构和水热力学进行详细分析，从而加快基于结构的药物发现。基本概念是将无均匀溶剂化理论（IST）的方程式离散到靶向结合位点的3D能量和熵的3D网格。这些网格将通过具有明确溶剂的分子动力学（MD）模拟来填充。所得的溶剂化处理（称为GIST）将通过与实验数据和严格的蛋白质结合口袋的热力学整合自由能计算进行比较来表征。 GIST方法将被纳入可视化工具中，以突出结合位点区域，在该区域特别有利或不利于置换溶剂，以加快配体设计并评估蛋白质结合口袋的“可药用性”。它还将集成到配体对接和评分的快速新功能中，该提案中为此提供了有希望的初步结果。最后，为了最大化科学和健康影响，软件 将作为免费提供，广泛使用和开源的Amber Tools软件套件包装，记录和传播。