基于分子对接和分子动力学模拟技术筛选SARS-CoV-23CL蛋白酶抑制剂  

Screening of SARS-CoV-23CL protease inhibitors based on molecular docking and molecular dynamics simulation technology

作　　者：吉冰洁 李尚校 王俭 边远 刘浩 赵勇山[2] JI Bingjie;LI Shangxiao;WANG Jian;BIAN Yuan;LIU Hao;ZHAO Yongshan(School of Medical Devices,Shenyang Pharmaceutical University,Benxi 117004,China;School of Life Science and Biopharmaceutical,Shenyang Pharmaceutical University,Benxi 117004,China)

机构地区：[1]沈阳药科大学医疗器械学院,辽宁本溪117004 [2]沈阳药科大学生命科学与生物制药学院,辽宁本溪117004

出　　处：《沈阳药科大学学报》2023年第8期1069-1077,1091,共10页Journal of Shenyang Pharmaceutical University

摘　　要：目的 以分子对接和分子动力学模拟技术相结合的方法筛选得到严重急性呼吸系统综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2,SARS-CoV-2) 3CL蛋白酶的小分子抑制剂。方法 基于SARS-CoV-2 3CL蛋白酶的晶体结构(PDB ID:7K3T和7SI9),从PubChem数据库中筛选得到SARS-CoV-2 3CL蛋白酶的特异性抑制剂nirmatrelvir的结构类似物,使用Autodock进行非共价分子对接,使用AutoDockFR进行共价分子对接,采用Pymol和Ligplot软件对SARS-CoV-2 3CL蛋白酶和小分子进行相互作用模式分析,最后使用AMBER18进行小分子化合物与SARS-CoV-2 3CL蛋白酶复合物的分子动力学模拟,进一步验证分子对接结果,使用SwissADME对化合物进行成药性分析。结果 将78个nirmatrelvir结构类似物与SARS-CoV-2 3CL蛋白酶进行虚拟筛选和分子对接,得到了2个与nirmatrelvir作用相当的小分子化合物(PubChem ID:57842182和156619968),共价对接发现化合物57842182和化合物156619968与SARS-CoV-2 3CL蛋白酶间不存在共价结合。分子动力学模拟结果表明化合物57842182、化合物156619968与SARS-CoV-2 3CL蛋白酶的结合自由能(ΔE_(total))分别为-23.96 kcal·mol^(-1)和-27.11 kcal·mol^(-1),二者主要通过与MET165、GLU166、ASN142、CYS145、LEU50、MET49等氨基酸残基的相互作用占据SARS-CoV-2 3CL蛋白酶亚活性位点,具有潜在抑制SARS-CoV-2 3CL蛋白酶活性的功能。化合物57842182和化合物156619968的成药性略差于nirmatrelvir。结论 筛选得到的nirmatrelvir结构类似物57842182和156619968具有作为新型冠状病毒SARS-CoV-2 3CL蛋白酶小分子抑制剂的潜力,其与SARS-CoV-2 3CL蛋白酶的结合特点可为SARS-CoV-2 3CL蛋白酶抑制剂的药物设计提供线索。Objective To screen the SARS-CoV-2 3CL protease inhibitors by molecular docking and molecular dynamics simulation technology.Methods Based on the crystal structure of SARS-CoV-2 3CL protease(PDB ID:7K3T and 7SI9),the structural analogue of inhibitor nirmatrelvir was screened fromPubChem database, and non-covalent molecular docking was performed using Autodock.We conducted covalent molecular docking of compounds to SARS-CoV-2 3CL protease using the AutoDockFR.Pymol and Ligplot software have been used to analyze the intermolecular interactions between docked compounds.The results were further validated by using AMBER18 for molecular dynamics simulations of complex compounds with SARS-CoV-2 3CL protease, and the druggability property of the compounds was evaluated by SwissADME.Results A virtual screening and molecular docking of 78 analogs of nirmatrelvir with SARS-CoV-2 3CL protease.Compounds(PubChem ID:57842182 and 156619968) with comparable binding energy to nirmatrelvir were obtained.It was found that there was no covalent binding between 57842182 and 156619968 and SARS-CoV-2 3CL protease.The binding energy of 57842182 and 156619968 with 3CL protease by Molecular dynamics simulation was-23.96 kcal·mol^(-1) and-27.11 kcal·mol^(-1),respectively.They preferably bind to S1-,S2-and S4-subpockets of SARS-CoV-2 3CL protease mainly through interaction with MET165,GLU166,ASN142,CYS145,LEU50,MET49 and other amino acid residues.They have the potential function of inhibiting SARS-CoV-2 3CL protease activity.57842182 and 156619968 are slightly less druggable than nirmatrelvir.Conclusion 57842182 and 156619968,the structural analogs of nirmatrelvir, was screened for their potential as inhibitor of SARS-CoV-2 3CL protease, and their binding characteristics to SARS-CoV-2 3CL protease may provide reference for drug design of SARS-CoV-2 3CL protease inhibitors.

关 键 词：新型冠状病毒 SARS-CoV-23CL蛋白酶 分子对接 分子动力学模拟 

分 类 号：R917[医药卫生—药物分析学]