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In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease

文献类型：期刊论文

作者Xiong, Muya2,3,4; Nie, Tianqing5; Shao, Qiang2,3; Li, Minjun1; Su, Haixia2,3; Xu, Yechun2,3,4,5,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-03-05
卷号231页码:8
关键词SARS-CoV-2 3C-Like protease Covalent inhibitor Virtual screening Crystal structure
ISSN号0223-5234
DOI10.1016/j.ejmech.2022.114130
通讯作者Su, Haixia(suhaixia1@simm.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn)
英文摘要The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease (3CL(pro)) has been regarded as an extremely promising antiviral target for the treatment of coronavirus disease 2019 (COVID-19). Here, we carried out a virtual screening based on commercial compounds database to find novel covalent non-peptidomimetic inhibitors of this protease. It allowed us to identify 3 hit compounds with potential covalent binding modes, which were evaluated through an enzymatic activity assay of the SARS-CoV-2 3CL(pro). Moreover, an X-ray crystal structure of the SARS-CoV-2 3CL(pro) in complex with compound 8, the most potent hit with an IC50 value of 8.50 mu M, confirmed the covalent binding of the predicted warhead to the catalytic residue C145, as well as portrayed interactions of the compound with S1' and S2 subsites at the ligand binding pocket. Overall, the present work not merely provided an experiment-validated covalent hit targeting the SARS-CoV-2 3CL(pro), but also displayed a prime example to seeking new covalent small molecules by a feasible and effective computational approach. (c) 2022 Elsevier Masson SAS. All rights reserved.
WOS关键词DESIGN ; MODEL
资助项目National Natural Science Foundation of China[21877122] ; National Natural Science Foundation of China[32071248] ; Science and Technology Commission of Shanghai Municipality[20430780300] ; Science and Technology Commission of Shanghai Municipality[19431901100] ; Sustainable Development of Precious Traditional Chinese Medicine Resources[2060302-2001-01]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000765974800002
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/299893]  
专题新药研究国家重点实验室
通讯作者Su, Haixia; Xu, Yechun
作者单位1.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Xiong, Muya,Nie, Tianqing,Shao, Qiang,et al. In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,231:8.
APA Xiong, Muya,Nie, Tianqing,Shao, Qiang,Li, Minjun,Su, Haixia,&Xu, Yechun.(2022).In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,231,8.
MLA Xiong, Muya,et al."In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 231(2022):8.

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来源：上海药物研究所

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