Structure-Based Discovery of Thiosemicarbazones As SARS-CoV-2 Main Protease Inhibitors

Abstract

<b>Aim:</b> Discovery of novel SARS-CoV-2 main protease (M^pro) inhibitors using a structure-based drug discovery strategy. <b>Materials & methods:</b> Virtual screening employing covalent and noncovalent docking was performed to discover M^pro inhibitors, which were subsequently evaluated in biochemical and cellular assays. <b>Results:</b> 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. <b>Conclusion:</b> This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 M^pro inhibitors.