Repurposing low–molecular-weight drugs against the main protease of severe acute respiratory syndrome coronavirus 2

The coronavirus disease (COVID-19) pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the global healthcare system. Drug repurposing is a feasible method for emergency treatment. 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 hit1binding to the catalytic pocket of the main protease of the SARS-CoV-2 (M^pro), thereby modestly inhibiting the enzymatic activity of M^pro. Chemical shift perturbations induced by niacin and hit1indicate a partial overlap of their binding sites, i.e., the catalytic pocket of M^promay accommodate derivatives with large molecular sizes. Therefore, we searched for drugs containing niacin or hit1pharmacophores and identified carmofur, bendamustine, triclabendazole, and emedastine; these drugs are highly capable of inhibiting protease activity. 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.