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.
【초록키워드】 COVID-19, SARS-CoV-2, coronavirus, pandemic, Drug discovery, Mortality, Antiviral, protease, in silico, inhibitors, Replication, serum, morbidity, cleavage, inhibitor, antiviral target, platform, SARS-CoV-2 replication, Concentration, acute respiratory syndrome, inhibitors of SARS-CoV-2, enzyme, Compound, M pro, analogue, effective, structure-based screening, identify, performed, develop, caused, facilitate, half-live, novel lineage, trichostatin A, 【제목키워드】 SARS-CoV-2 main protease, inhibitor,