Solvation directed drug design: from molecular physics to lead optimization

项目摘要 该项目旨在开发新的方法和计算工具，以加速基于结构的药物- 发现并应用这些方法来鉴定μ-阿片受体和SARS的新的先导药物候选物- CoV-2主要蛋白酶。这将通过提供水化结构的详细分析来完成， 然后将该信息结合到对接中， 水基药效团虚拟筛选。主要目标是开发分析工具， 然后利用这些溶剂化结构图和热力学图， 改进结合袋可药性计算方法，可购化合物的虚拟筛选 数据库和合理的铅修改。虚拟筛选新方法的初步结果， 结合基于水-蛋白质相互作用的药效团构建与ROCS快速形状和模式 匹配表明，该方法比计算对接快3个数量级以上。

Project Summary This project aims to develop new methods and computational tools that will speed structure-based drug- discovery and apply these methods to identify new lead drug candidates for the mu-opioid receptor and SARS- CoV-2 main proteases. This will be accomplished by providing a detailed analysis of hydration structure and thermodynamics in targeted protein binding pockets then incorporating this information into docking and water-based pharmacophore virtual screens. Key aims are to develop analysis tools that characterize and map out solvation on the surfaces of drug target then utilize these solvation structural and thermodynamic maps to improve computational methods of binding pocket druggability, virtual screening of purchasable compound databases, and rational lead modification. Preliminary results for a new method of virtual screening that combines constructing pharmacophores based on water-protein interactions with ROCS fast shape and pattern matching show the method is greater than 3 orders of magnitude faster than computational docking.