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

• Published in: Future medicinal chemistry Vol. 15; no. 11; pp. 959 - 985
• Main Authors: Maltarollo, Vinícius Gonçalves, da Silva, Elany Barbosa, Kronenberger, Thales, Sena Andrade, Marina Mol, de Lima Marques, Gabriel V, Cândido Oliveira, Nereu J, Santos, Lucianna H, Oliveira Rezende Júnior, Celso de, Cassiano Martinho, Ana C, Skinner, Danielle, Fajtová, Pavla, M Fernandes, Thaís H, Silveira Dos Santos, Eduardo da, Rodrigues Gazolla, Poliana A, Martins de Souza, Ana P, da Silva, Milene Lopes, Dos Santos, Fabíola S, Lavorato, Stefânia N, Oliveira Bretas, Ana C, Carvalho, Diogo Teixeira, Franco, Lucas Lopardi, Luedtke, Stephanie, Giardini, Miriam A, Poso, Antti, Dias, Luiz C, Podust, Larissa M, Alves, Ricardo J, McKerrow, James, Andrade, Saulo F, Teixeira, Róbson R, Siqueira-Neto, Jair L, O'Donoghue, Anthony, de Oliveira, Renata B, Ferreira, Rafaela S
• Format: Journal Article
• Language: English
• Published: England Newlands Press Ltd 01.06.2023
• Subjects: computer-aided drug design; coronavirus; molecular docking; molecular dynamics simulations; protease inhibitors; SARS-CoV-2; virtual screening; molecular dynamics simulations; SARS-CoV-2; molecular docking; Mpro; virtual screening; protease inhibitors; coronavirus; computer-aided drug design
• ISSN: 1756-8919; 1756-8927
• DOI: 10.4155/fmc-2023-0034

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