Structure-based discovery of thiosemicarbazones as SARS-CoV-2 main protease inhibitors.
Vinícius Gonçalves MaltarolloElany Barbosa da SilvaThales KronenbergerMarina Mol Sena AndradeGabriel V de Lima MarquesNereu J Cândido OliveiraLucianna H SantosCelso de Oliveira Rezende JúniorAna C Cassiano MartinhoDanielle SkinnerPavla FajtováThaís H M FernandesEduardo da Silveira Dos SantosPoliana A Rodrigues GazollaAna P Martins de SouzaMilene Lopes da SilvaFabíola S Dos SantosStefânia N LavoratoAna C Oliveira BretasDiogo Teixeira CarvalhoLucas Lopardi FrancoStephanie LuedtkeMiriam A GiardiniAntti PosoLuiz C DiasLarissa M PodustRicardo J AlvesJames McKerrowSaulo F AndradeRóbson R TeixeiraJair L Siqueira-NetoAnthony O'DonoghueRenata Barbosa de OliveiraRafaela Salgado FerreiraPublished in: Future medicinal chemistry (2023)
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 IC 50 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.