Department of Computer Science, School of Computing, Tokyo Institute of Technology, Tokyo 152-8550, Japan.
Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
J Chem Inf Model. 2021 Jun 28;61(6):2744-2753. doi: 10.1021/acs.jcim.1c00134. Epub 2021 Jun 1.
Cosolvent molecular dynamics (CMD) simulations involve an MD simulation of a protein in the presence of explicit water molecules mixed with cosolvent molecules to perform hotspot detection, binding site identification, and binding energy estimation, while other existing methods (e.g., MixMD, SILCS, and MDmix) utilize small molecules that represent functional groups of compounds. However, the cosolvent selections employed in these methods differ and there are only a few cosolvents that are commonly used in these methods. In this study, we proposed a systematic method for constructing a set of cosolvents for drug discovery, termed the EXtended PRObes set construction by REpresentative Retrieval (EXPRORER). First, we extracted typical substructures from FDA-approved drugs, generated 138 cosolvent structures, and for each cosolvent molecule, we conducted CMD simulations to generate a spatial probability distribution map of cosolvent atoms (PMAP). Analyses of PMAP similarity revealed that a cosolvent pair with a PMAP similarity greater than 0.70-0.75 shared similar structural features. We present a method for the construction of a cosolvent subset that satisfies a similarity threshold for all cosolvents, and we tested the constructed sets for four proteins. To our knowledge, this is the first study to include a systematic proposal for cosolvent set construction, and thus, the EXPRORER cosolvents will provide deeper insights into ligand binding sites of various proteins.
共溶剂分子动力学 (CMD) 模拟涉及在存在显式水分子和共溶剂分子的情况下对蛋白质进行 MD 模拟，以进行热点检测、结合位点识别和结合能估计，而其他现有方法（例如 MixMD、SILCS 和 MDmix）则利用代表化合物官能团的小分子。然而，这些方法中使用的共溶剂选择不同，并且这些方法中常用的共溶剂只有几种。在这项研究中，我们提出了一种用于药物发现的共溶剂构建的系统方法，称为通过代表性检索构建的扩展探针集（EXPRORER）。首先，我们从 FDA 批准的药物中提取典型的亚结构，生成了 138 个共溶剂结构，对于每个共溶剂分子，我们进行了 CMD 模拟，生成了共溶剂原子的空间概率分布图 (PMAP)。PMAP 相似性分析表明，PMAP 相似性大于 0.70-0.75 的共溶剂对具有相似的结构特征。我们提出了一种构建满足所有共溶剂相似性阈值的共溶剂子集的方法，并针对四种蛋白质对构建的集合进行了测试。据我们所知，这是第一项包括共溶剂集构建系统建议的研究，因此，EXPRORER 共溶剂将为各种蛋白质的配体结合位点提供更深入的见解。
