EXPRORER: Rational Cosolvent Set Construction Method for Cosolvent Molecular Dynamics Using Large-Scale Computation
EXPRORER: Rational Cosolvent Set Construction Method for Cosolvent Molecular Dynamics Using Large-Scale Computation
复制标题
EXPRORER：利用大规模计算的共溶剂分子动力学的合理共溶剂集构建方法
DOI：
10.1021/acs.jcim.1c00134
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发表时间：
2021
影响因子：
5.6
通讯作者：
Shimizu Kentaro
中科院分区：
文献类型：
--
作者：
Yanagisawa Keisuke;Moriwaki Yoshitaka;Terada Tohru;Shimizu Kentaro
共溶剂分子动力学（CMD）模拟涉及在显式水分子与共溶剂分子混合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（如MixMD、SILCS和MDmix）利用代表化合物官能团的小分子。然而，在这些方法中使用的共溶剂选择不同，只有少数几种共溶剂在这些方法中常用。在这项研究中，我们提出了一种系统的方法来构建一组用于药物发现的共溶剂，称为扩展探针集构建代表检索（EXPRORER）。首先，我们从fda批准的药物中提取典型的亚结构，生成138个共溶剂结构，并对每个共溶剂分子进行CMD模拟，生成共溶剂原子的空间概率分布图（PMAP）。PMAP相似度分析表明，PMAP相似度大于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共溶剂子集的方法，该方法满足所有共溶剂的相似性阈值，并对四种蛋白质的构建集进行了测试。据我们所知，这是第一个包含系统构建共溶剂集的研究，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了解。
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.