Integration of structural and dynamic aspects of drug resistance into drug design

项目摘要 将耐药性的结构和动力学方面整合到药物设计中 项目3 -谢尔曼，薛定谔公司 我们将开发基于结构的工具来帮助分析和预测耐药突变。 我们将整合基板信封假设到一个对接算法来考虑阻力 在虚拟筛选期间进行突变。我们还将使用自由能方法来评估假定的 耐药突变潜在耐药突变的列表将来自由以下人员进行的深度测序： 项目2.首先，我们将开发一套工具，用于利用深层序列信息来生成可能的 抗性突变体此外，我们将使用分子生物学方法研究结合位点远端的耐药突变。 动力学和互信息理论。最后，我们将探讨明确的水分子对 使用分子动力学和非均相溶剂化理论的组合的耐药性。这 一种综合方法，包括实验、经验和基于物理的方法，应增加 这对设计具有更好抗性的缓蚀剂具有重要价值。

Project Summary Integration of structural and dynamic aspects of drug resistance into drug design Project 3 - Sherman, Schrodinger Inc. We will be developing structure-based tools to aid in the analysis and prediction of drug resistance mutations. We will integrate the substrate envelope hypothesis into a docking algorithm to account for resistance mutations during virtual screening. We will also use free energy methods to assess the impact of putative resistance mutations. The list of potential resistance mutations will come from deep sequencing performed by Project 2. First, we will develop a suite of tools for utilizing deep sequence information to generate possible resistant mutants. In addition, we will study resistance mutations distal from the binding site using molecular dynamics and mutual information theory. Finally, we will explore the importance of explicit water molecules on drug resistance using a combination of molecular dynamics and inhomogeneous solvation theory. This combined approach, which includes experimental, empirical, and physics-based approaches, should add significant value to the design of inhibitors with better resistance profiles.