1. Structure-based discovery of thiosemicarbazones as SARS-CoV-2 main protease inhibitors.
- Author
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Maltarollo VG, da Silva EB, Kronenberger T, Sena Andrade MM, de Lima Marques GV, Cândido Oliveira NJ, Santos LH, Oliveira Rezende Júnior C, Cassiano Martinho AC, Skinner D, Fajtová P, M Fernandes TH, Silveira Dos Santos ED, Rodrigues Gazolla PA, Martins de Souza AP, da Silva ML, Dos Santos FS, Lavorato SN, Oliveira Bretas AC, Carvalho DT, Franco LL, Luedtke S, Giardini MA, Poso A, Dias LC, Podust LM, Alves RJ, McKerrow J, Andrade SF, Teixeira RR, Siqueira-Neto JL, O'Donoghue A, de Oliveira RB, and Ferreira RS
- Subjects
- Humans, SARS-CoV-2, Antiviral Agents pharmacology, Antiviral Agents chemistry, Molecular Docking Simulation, Protease Inhibitors pharmacology, Protease Inhibitors chemistry, Viral Nonstructural Proteins, COVID-19, Thiosemicarbazones pharmacology
- Abstract
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 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.- Published
- 2023
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