基于分子对接虚拟筛选铜绿假单胞菌胞外酶exoS抑制剂的研究  

Research of exoS inhibitors of pseudomonas aeruginosa byvirtual screening based on molecular docking

作　　者：陈双扣[1] 唐思 谭小庆 徐曦 任风鸣[2] 管天冰 孙静怡 胡新龙 CHEN Shuang-kou;TANG Si;TAN Xiao-qing;XU Xi;REN Feng-ming;GUAN Tian-bing;SUN Jing-yi;HU Xin-long(Department of chemistry and chemical engineering,Chongqing University of Science and Technology,Chongqing 401331,China;Institute of Medicinal Plant Cultivation,Chongqing 408435,China)

机构地区：[1]重庆科技学院化学化工学院,重庆401331 [2]重庆市药物种植研究所,重庆408435

出　　处：《化学研究与应用》2023年第7期1624-1634,共11页Chemical Research and Application

基　　金：重庆英才计划-创新创业示范团队项目(CQYC20210309793)资助;重庆英才计划-基础研究与前沿探索项目(cstc2022ycjhbgzxm0029)资助。

摘　　要：铜绿假单胞菌是引起宿主防御机制受损患者严重感染的重要原因。胞外酶S(exoS)为铜绿假单胞菌III型分泌系统(T3SS)分泌的毒力因子之一,是维持细菌在宿主体内繁殖的重要步骤。因此,本文首先运用虚拟筛选的方法学研究,确定exoS的6GNJ靶点蛋白为应用于分子对接虚拟筛选的最佳对接模型。随后利用分子对接、结构相似性筛选和类药性评价等多种策略,从中药系统药理学数据库与分析平台(TCMSP)数据库中筛选出4个命中分子。分子对接显示MOL008550和MOL001870与exoS受体蛋白具有强氢键作用和疏水相互作用,表现出较高的结合亲和力,为前2位最佳命中分子。结合分子动力学模拟分析发现,MOL008550和MOL001870与exoS受体蛋白的复合物比参考化合物(F4W501)具有更有利的动态稳定性。结合自由能计算显示,MOL008550和MOL001870的结合自由能强于F4W501,且与exoS受体蛋白的作用方式和F4W501类似,主要为静电、疏水作用及范德华力促进两者间的结合,其可能对exoS表现出更高的抑制活性,为潜在的exoS靶向小分子抑制剂。虚拟筛选活性化合物并探究其与胞外酶S的互作模式及动力学稳定性,为开发新型的高效靶向exoS抑制剂提供了研究思路和物质参考。Pseudomonas aeruginosa is an important cause of severe infections in patients with impaired host defense mechanisms.Enzyme S(exoS)is one of the virulence factors secreted by the type III secretion system(T3SS)of Pseudomonas aeruginosa,which is an important step to maintain bacterial reproduction in the host.Therefore,We first used the methodology of virtual screening to de-termine the 6GNJ target protein of exoS as the best docking model for virtual screening based on molecular docking.Then 4 hit mol-ecules were mined from the TCMSP database by molecular docking,structural similarity screening,and drug-like evaluation.Molec-ular docking showed that MOL008550 and MOL001870 had strong hydrogen bonding and hydrophobic interaction with exoS receptor proteins,showing high binding affinity,and were the top two best hit molecules.Combined with molecular dynamics simulation anal-ysis,it was found that the complexes formed by MOL008550 and MOL001870 with exoS receptor proteins showed more favorable dy- namic stability than the reference compounds(F4W501). The calculation of binding free energy showed that MOL008550 andMOL001870 had stronger binding free energy than that of F4W501,and had similar modes of action with F4W501,mainly electro-static,hydrophobic and van der Waals force promoted the binding between protein and ligand,which might show higher inhibitoryactivity on exoS,and they were potential exoS-targeting small molecule inhibitors. The active compounds were virtual screened andthe interaction pattern and kinetic stability of the active compounds with exoS were explored to provide research ideas and materialreferences for the development of novel efficient exoS-targeting inhibitors.

关 键 词：铜绿假单胞菌 胞外酶 分子对接 虚拟筛选 分子动力学模拟 

分 类 号：R284[医药卫生—中药学]