Title: In silico Studies on the Interaction between Mpro and PLpro From SARS-CoV-2 and Ebselen, its Metabolites and Derivatives.
Authors: Nogara, Pablo Andrei; Omage, Folorunsho Bright; Bolzan, Gustavo Roni; Delgado, Cássia Pereira; Aschner, Michael; Orian, Laura; Teixeira Rocha, João Batista
Published In Mol Inform, (2021 Aug)
Abstract: The COVID-19 pandemic caused by the SARS-CoV-2 has mobilized scientific attention in search of a treatment. The cysteine-proteases, main protease (Mpro) and papain-like protease (PLpro) are important targets for antiviral drugs. In this work, we simulate the interactions between the Mpro and PLpro with Ebselen, its metabolites and derivatives with the aim of finding molecules that can potentially inhibit these enzymes. The docking data demonstrate that there are two main interactions between the thiol (-SH) group of Cys (from the protease active sites) and the electrophilic centers of the organoselenium molecules, i. e. the interaction with the carbonyl group (O=C… SH) and the interaction with the Se moiety (Se… SH). Both interactions may lead to an adduct formation and enzyme inhibition. Density Functional Theory (DFT) calculations with Ebselen indicate that the energetics of the thiol nucleophilic attack is more favorable on Se than on the carbonyl group, which is in accordance with experimental data (Jin et al. Nature, 2020, 582, 289-293). Therefore, organoselenium molecules should be further explored as inhibitors of the SARS-CoV-2 proteases. Furthermore, we suggest that some metabolites of Ebselen (e. g. Ebselen diselenide and methylebselenoxide) and derivatives ethaselen and ebsulfur should be tested in vitro as inhibitors of virus replication and its proteases.
PubMed ID: 34018687
MeSH Terms: Antiviral Agents/chemistry; Antiviral Agents/metabolism; Antiviral Agents/pharmacology; Azoles/chemistry; Azoles/metabolism; Azoles/pharmacology*; COVID-19 Drug Treatment*; COVID-19/metabolism; Catalytic Domain/drug effects; Coronavirus Papain-Like Proteases/antagonists & inhibitors; Coronavirus Papain-Like Proteases/metabolism*; Drug Discovery; Humans; Isoindoles; Molecular Docking Simulation; Organoselenium Compounds/chemistry; Organoselenium Compounds/metabolism; Organoselenium Compounds/pharmacology*; Protease Inhibitors/chemistry; Protease Inhibitors/metabolism; Protease Inhibitors/pharmacology*; SARS-CoV-2/drug effects*; Viral Matrix Proteins/antagonists & inhibitors; Viral Matrix Proteins/metabolism*