Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode  

新冠病毒主蛋白酶与天然产物抑制剂紫草素的复合物晶体结构揭示一种独特的抑制剂结合模式

作　　者：Jian Lia Xuelan Zhou Yan Zhang Fanglin Zhong Cheng Lin Peter J.McCormick Feng Jiang Jun Luo Huan Zhou Qisheng Wang Yang Fu Jingjing Duan Jin Zhang 李健;周学兰;张焱;钟芳林;林程;Peter J.McCormick;江峰;罗军;周欢;汪启胜;傅暘;段晶晶;张进(College of Pharmaceutical Sciences,Gannan Medical University,Ganzhou 341000,China;School of Basic Medical Sciences,Nanchang University,Nanchang 330031,China;The Second Affiliated Hospital of Nanchang University,Nanchang 330031,China;Shenzhen Crystalo Biopharmaceutical Co.,Ltd,Shenzhen 518118,China;Jiangxi Jmerry Biopharmaceutical Co.,Ltd.Ganzhou 341000,China;Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases,Ministry of Education,Gannan Medical University,Ganzhou 341000,China;William Harvey Research Institute,Ban's and the London School of Medicine and Dentistry,Queen Mary University of London,London EC1M 6BQ,UK;Shanghai Synchrotron Radiation Facility,Shanghai Advanced Research Institute,Chinese Academy of Sciences,Shanghai 201204,China;School of Medicine,Southern University of Science and Technology,Shenzhen 518055,China;Human Aging Research Institute(HARI),School of Life Sciences,Nanchang University,Nanchang 330031,China)

机构地区：[1]College of Pharmaceutical Sciences,Gannan Medical University,Ganzhou 341000,China [2]School of Basic Medical Sciences,Nanchang University,Nanchang 330031,China [3]The Second Affiliated Hospital of Nanchang University,Nanchang 330031,China [4]Shenzhen Crystalo Biopharmaceutical Co.,Ltd,Shenzhen 518118,China [5]Jiangxi Jmerry Biopharmaceutical Co.,Ltd.Ganzhou 341000,China [6]Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases,Ministry of Education,Gannan Medical University,Ganzhou 341000,China [7]William Harvey Research Institute,Ban's and the London School of Medicine and Dentistry,Queen Mary University of London,London EC1M 6BQ,UK [8]Shanghai Synchrotron Radiation Facility,Shanghai Advanced Research Institute,Chinese Academy of Sciences,Shanghai 201204,China [9]School of Medicine,Southern University of Science and Technology,Shenzhen 518055,China [10]Human Aging Research Institute(HARI),School of Life Sciences,Nanchang University,Nanchang 330031,China

出　　处：《Science Bulletin》2021年第7期661-663,M0003,共4页科学通报（英文版）

基　　金：supported by the Thousand Young Talents Program of China;the National Natural Science Foundation of China(31770795,81974514,21961003;31971043);the Jiangxi Provincial Natural Science Foundation(20181ACB20014 and20192BAB205114);the Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases,Ministry of Education(XN201904);Gannan Medical University(QD201910);Jiangxi"Double Thousand Plan";the Foreign Talent Project of Jiangxi Province;Talent Project of Jiangxi Province;Shenzhen Fundamental Research Program;Ganzhou COVID-19 Emergency Research Project。

摘　　要：Almost everyone is susceptible to the severe acute respiratorysyndrome coronavirus 2(SARS-CoV-2),an RNA virus,which cancause many symptoms and even death among high-risk individu-als[1,2].The main protease(M^(Pro),also known as 3CL^(Pro))is a cys-teine protease essential for producing infectious virions and thusan attractive target for drug development.Up to now,many studiesusing either in silico ligand docking or drug discovery based onavailable structures have been performed to discover new MPTO.inhibiting agents[3.4].人们对于中药活性成分如何抑制新冠病毒的分子机制尚不完全了解.主蛋白酶(Mpro,又称3CLpro)在冠状病毒生命周期的复制中起着重要作用,是治疗冠状病毒最有潜力的药物靶点之一.紫草素是中药紫草的根的主要活性成分,具有抗病毒、抗菌、抗炎和抗肿瘤的作用. SARS-Co V-2主蛋白酶与紫草素结合的晶体结构表明,紫草素以一种独特的方式与主蛋白酶结合,其萘醌基团位于催化活性位点His41和Cys145之间,与His41形成π-π相互作用.本文揭示中药活性成分紫草素抑制新冠病毒主蛋白酶的分子机制,发现紫草素在结合口袋的结合方式非常独特,不同于现有的小分子抑制剂结合模式,对于针对主蛋白酶这一靶点的药物研发可能有重要意义.

关 键 词：小分子抑制剂 紫草素 冠状病毒 药物研发 药物靶点 天然产物 中药活性成分 结合模式 

分 类 号：TQ460.1[化学工程—制药化工]