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，通过提供对靶向蛋白质结合口袋中水的水合结构和热力学的详细分析，加快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）的方程离散化，直到二阶，到目标结合位点的能量和熵的3D网格上。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。由此产生的治疗溶剂化，称为GIST，其特征在于通过与实验数据和严格的热力学积分自由能计算蛋白结合口袋的比较。GIST方法将被纳入可视化工具中，以突出显示特别有利于或不利于取代溶剂的结合位点区域，以加速配体设计并评估蛋白质结合口袋的“可药用性”。它也将被集成到快速的配体对接和评分，其中有前途的初步结果，在这个建议的新功能。最后，为了最大限度地发挥科学和健康影响， 将被打包，记录和传播的一部分，免费提供，广泛使用和开源的琥珀工具软件套件。

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.