Repurposing Low-Molecular-Weight Drugs against the Main Protease of Severe Acute Respiratory Syndrome Coronavirus 2

作者：Jia Gao, Liang Zhang, Xiaodan Liu, Fudong Li, Rongsheng Ma, Zhongliang Zhu, Jiahai Zhang, Jihui Wu, Yunyu Shi, Yueyin Pan, Yushu Ge, Ke Ruan · 发表于：The Journal of Physical Chemistry Letters · 年份：2020 · DOI：10.1021/acs.jpclett.0c01894 · 被引用次数：26 · 研究领域：Computational Drug Discovery Methods、SARS-CoV-2 and COVID-19 Research、vaccines and immunoinformatics approaches

High Resolution Image Download MS PowerPoint Slide The coronavirus disease pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the global healthcare system. As low-molecular-weight drugs have high potential to completely match interactions with essential SARS-CoV-2 targets, we propose a strategy to identify such drugs using the fragment-based approach. Herein, using ligand- and protein-observed fragment screening approaches, we identified niacin and hit 1 binding to the catalytic pocket of the main protease (M pro ) of SARS-CoV-2, thereby modestly inhibiting the enzymatic activity of M pro . We further searched for low-molecular-weight drugs containing niacin or hit 1 pharmacophores with enhanced inhibiting activity, e.g., carmofur, bendamustine, triclabendazole, emedastine, and omeprazole, in which omeprazole is the only one binding to the C-terminal domain of SARS-CoV-2 M pro . Our study demonstrates that the fragment-based approach is a feasible strategy for identifying low-molecular-weight drugs against the SARS-CoV-2 and other potential targets lacking specific drugs.