Structure-Based Discovery of Thiosemicarbazones As SARS-CoV-2 Main Protease Inhibitors
Vinícius Gonçalves Maltarollo, Elany Barbosa da Silva, Thales Kronenberger, Marina Mol Sena Andrade, Gabriel Marques, Nereu Junio Cândido Oliveira, Lucianna Helene Santos, Celso de Oliveira Rezende Júnior, Ana Clara Cassiano Martinho, Danielle Skinner, Pavla Fajtová, Thaís Helena Maciel Fernandes, Eduardo da Silveira dos Santos, Poliana Aparecida Rodrigues Gazolla, Ana Paula Martins de Souza, Milene Lopes da Silva, Fabíola S dos Santos, Stefânia Neiva Lavorato, Ana Carolina Oliveira Bretas, Diogo Teixeira Carvalho · Future Medicinal Chemistry · 2023
Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro 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 Mpro with IC50 values of 0.4–3 μM. They were also shown to inhibit SARS-CoV-1 Mpro and human cathepsin L. Molecular dynamics simulations indicated the stability of the Mpro 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 Mpro inhibitors.