Int J Biol Sci 2021; 17(6):1555-1564. doi:10.7150/ijbs.59191

Research Paper

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

Lei Wen1*, Kaiming Tang1*, Kenn Ka-Heng Chik1, Chris Chun-Yiu Chan1, Jessica Oi-Ling Tsang1, Ronghui Liang1, Jianli Cao1, Yaoqiang Huang1, Cuiting Luo1, Jian-Piao Cai1, Zi-Wei Ye1, Feifei Yin2,3,4✉, Hin Chu1, Dong-Yan Jin5, Kwok-Yung Yuen1,3,6, Shuofeng Yuan1✉, Jasper Fuk-Woo Chan6✉

1. State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
2. Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan, China.
3. Hainan-Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, Hainan, and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
4. Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan, China.
5. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
6. Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China.
*Equal contribution.

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Citation:
Wen L, Tang K, Chik KKH, Chan CCY, Tsang JOL, Liang R, Cao J, Huang Y, Luo C, Cai JP, Ye ZW, Yin F, Chu H, Jin DY, Yuen KY, Yuan S, Chan JFW. In silico structure-based discovery of a SARS-CoV-2 main protease inhibitor. Int J Biol Sci 2021; 17(6):1555-1564. doi:10.7150/ijbs.59191. Available from https://www.ijbs.com/v17p1555.htm

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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 (Mpro) 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 Mpro 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 Mpro 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.