In Vitro and in Silico Studies of Potential Coronavirus-Specific 3C-Like Protease Inhibitors

• Published in: Chemical & pharmaceutical bulletin Vol. 70; no. 3; pp. 195 - 198
• Main Authors: Maehara, Shoji, Kobayashi, Manami, Kuwada, Mari, Choshi, Tominari, Inoue, Hirofumi, Hieda, Yuhzou, Nishiyama, Takashi, Hata, Toshiyuki
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.03.2022; Japan Science and Technology Agency
• Subjects: 3C-like protease; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Coronaviruses; COVID-19 - drug therapy; ebselen; Free energy; Humans; Michael reaction; molecular modeling; phenyl-benzothiazol-3-one; Protease; Protease inhibitors; Protease Inhibitors - pharmacology; Proteinase inhibitors; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; 3C-like protease; ebselen; phenyl-benzothiazol-3-one; molecular modeling; severe acute respiratory syndrome coronavirus 2
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c21-01002

We investigated similar compounds to ebselen and tideglusib, which exhibit strong activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using Molecular ACCess System (MACCS) keys. Four candidate compounds were identified. One of them, phenyl-benzothiazol-3-one, showed coronavirus-specific 3C-like (3CL) protease inhibitory activity. The results indicated that a similarity score above 0.81 is a good indicator of activity for ebselen-and-tideglusib-like compounds. Subsequently, we simulated the ring-cleavage Michael reaction of ebselen at the Se center, which is responsible for its 3CL protease inhibitory activity, and determined the activation free energy of the reaction. The results showed that reaction simulation is a useful tool for estimating the activity of inhibitory compounds that undergo Michael addition reactions with the relevant cysteine S atom of 3CL proteases.