<i>In silico</i> 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
Abstract
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 2.7M, which was markedly below its 50% effective cytotoxic concentration (75.7M) and peak serum concentration (132M). 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.