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。其基本概念是将不均匀溶剂化理论（IST）的方程离散化，直到二阶，到目标结合位点的能量和熵的三维网格上。这些网格将由带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严格的蛋白质结合口袋的热力学积分自由能计算来表征。GIST方法将被整合到可视化工具中，以突出特别有利于或不适合取代溶剂的结合位点区域，从而加快配体设计和评估蛋白质结合口袋的“药物性”。它还将集成到配体对接和评分的快速新功能中，本提案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的影响，软件

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.