In silico structure-based discovery of a SARS-CoV-2 main protease inhibitor

Wen, Lei; Tang, Kaiming; Chik, Kenn Ka-Heng; Chan, Chris Chun-Yiu; Tsang, Jessica Oi-Ling; Liang, Ronghui; Cao, Jianli; Huang, Yaoqiang; Luo, Cuiting; Cai, Jian-Piao; Ye, Zi-Wei; Yin, Feifei; Chu, Hin; Jin, Dong-Yan; Yuen, Kwok-Yung; Yuan, Shuofeng; Chan, Jasper Fuk-Woo

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.