Repurposing low-molecular-weight drugs against the main protease of SARS-CoV-2

The pandemic of COVID-19, which is caused by the SARS-CoV-2 virus infection, has posed a threat to global healthcare system. The repurposing drug is one of the feasible ways for the emergency treatment. As the low-molecular-weight drugs have a higher possibility to fully match the interactions with essential targets of SARS-CoV-2, we propose a strategy to uncover such drugs using the fragment-based approach.Here, using the ligand-observed and protein-observed fragment screening approach, we identified niacin and hit binding to the catalytic pocket of the main protease of SARS-CoV-2 (M), thus modestlyinhibited the enzymatic activity of M.The chemical shift perturbations induced by niacin and hit indicates a partial overlap of their binding sites, i.e., the catalytic pocket of M may accommodate derivatives with larger molecular size. We hence searched drugs containing the niacin or hit pharmocophore,and uncovered carmofur, bendamustine, triclabendazole and emedastine, which demonstrated higher potency of inhibiting protease activity than the fragment screening hits. Our work demonstrated that fragment-based approach is a feasible way to uncover low-molecular-weight drugs against SARS-CoV-2, and potentially other targets without specific drug yet.