In silico structure-based discovery of a SARS-CoV-2 main protease inhibitor
Lei Wen, Kaiming Tang, Kenn Ka‐Heng Chik, Chris Chun-Yiu Chan, Jessica Oi‐Ling Tsang, Ronghui Liang, Jianli Cao, Yaoqiang Huang, Cuiting Luo, Jian‐Piao Cai, Zi‐Wei Ye, Feifei Yin, Hin Chu, Dong‐Yan Jin, Kwok‐Yung Yuen, Shuofeng Yuan, Jasper Fuk‐Woo Chan · International Journal of Biological Sciences · 2021
The Coronavirus Disease 2019 (COVID-19) pandemic caused by the novel lineage B betacoroanvirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant mortality, morbidity, and socioeconomic disruptions worldwide.Effective antivirals are urgently needed for COVID-19.The main protease (M pro ) of SARS-CoV-2 is an attractive antiviral target because of its essential role in the cleavage of the viral polypeptide.In this study, we performed an in silico structure-based screening of a large chemical library to identify potential SARS-CoV-2 M pro inhibitors.Among 8,820 compounds in the library, our screening identified trichostatin A, a histone deacetylase inhibitor and an antifungal compound, as an inhibitor of SARS-CoV-2 M pro activity and replication.The half maximal effective concentration of trichostatin A against SARS-CoV-2 replication was 1.5 to 2.7µM, which was markedly below its 50% effective cytotoxic concentration (75.7µM) and peak serum concentration (132µM).Further drug compound optimization to develop more stable analogues with longer half-lives should be performed.This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of SARS-CoV-2.