Structure-based discovery of thiosemicarbazones as SARS-CoV-2 main protease inhibitors

Aim: Discovery of novel SARS-CoV-2 main protease (M^pro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover M^pro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 M^pro with IC₅₀ values of 0.4-3 μM. They were also shown to inhibit SARS-CoV-1 M^pro and human cathepsin L. Molecular dynamics simulations indicated the stability of the M^pro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 M^pro inhibitors.