Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Canrong Wu; Yang Liu; Yueying Yang; Peng Zhang; Wu Zhong; Yali Wang; Qiqi Wang; Yang Xu; Mingxue Li; Xingzhou Li; Mengzhu Zheng; Lixia Chen; Hua Li

doi:10.1016/j.apsb.2020.02.008

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Acta Pharm Sin B. 2020 May;10(5):766-788. doi: 10.1016/j.apsb.2020.02.008. Epub 2020 Feb 27.

Authors

Canrong Wu¹, Yang Liu², Yueying Yang², Peng Zhang², Wu Zhong³, Yali Wang², Qiqi Wang², Yang Xu², Mingxue Li², Xingzhou Li³, Mengzhu Zheng¹, Lixia Chen², Hua Li^{1

2}

Affiliations

¹ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.

Abstract

SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

Keywords: 3CLpro, 3-chymotrypsin-like protease; Drug repurposing; E, envelope; Homology modeling; M, membrane protein; Molecular docking; N, nucleocapsid protein; Nsp, non-structure protein; ORF, open reading frame; PDB, protein data bank; RdRp, RNA-Dependence RNA polymerase; Remdesivir; S, Spike; SARS-CoV-2; SUD, SARS unique domain; UB, ubiquitin-like domain.