tetano
Editor, Senior Moderator
J Phys Chem Lett
. 2020 Jul 28.
doi: 10.1021/acs.jpclett.0c01894. Online ahead of print.
Repurposing Low-Molecular-Weight Drugs Against the Main Protease of Severe Acute Respiratory Syndrome Coronavirus 2
Jia Gao, Liang Zhang, Xiaodan Liu, Fudong Li, Rongsheng Ma, Zhongliang Zhu, Jiahai Zhang, Jihui Wu, Yunyu Shi, Yueyin Pan, Yushu Ge, Ke Ruan
Abstract
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 (Mpro) of SARS-CoV-2, thereby modestly inhibiting the enzymatic activity of Mpro. 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 Mpro. 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.
. 2020 Jul 28.
doi: 10.1021/acs.jpclett.0c01894. Online ahead of print.
Repurposing Low-Molecular-Weight Drugs Against the Main Protease of Severe Acute Respiratory Syndrome Coronavirus 2
Jia Gao, Liang Zhang, Xiaodan Liu, Fudong Li, Rongsheng Ma, Zhongliang Zhu, Jiahai Zhang, Jihui Wu, Yunyu Shi, Yueyin Pan, Yushu Ge, Ke Ruan
- PMID: 32787337
- DOI: 10.1021/acs.jpclett.0c01894
Abstract
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 (Mpro) of SARS-CoV-2, thereby modestly inhibiting the enzymatic activity of Mpro. 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 Mpro. 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.