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

描述(由申请人提供)：该项目旨在开发新的计算工具，通过提供对目标蛋白质结合口袋中水的水合结构和热力学的详细分析，加速基于结构的药物发现。其基本概念是将非均匀溶剂化理论(IST)的方程离散到目标结合位上的能量和熵的3D网格上，直到二阶。这些网格将用显式溶剂的分子动力学(MD)模拟来填充。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口袋的严格热力学积分自由能计算来表征。GIST方法将被结合到可视化工具中，突出显示特别有利于或不利于置换溶剂的结合部位区域，以加快配基设计和评估蛋白质结合口袋的“可药性”。它还将被集成到配体对接和评分的快速新功能中，这一提议提供了有希望的初步结果。最后，为了最大限度地增加科学和健康影响，该软件 将作为免费提供、广泛使用和开源的琥珀工具软件套件的一部分进行打包、记录和分发。

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.