TY - JOUR
T1 - In silico Studies on the Interaction between Mpro and PLpro From SARS-CoV-2 and Ebselen, its Metabolites and Derivatives
AU - Nogara, Pablo Andrei
AU - Omage, Folorunsho Bright
AU - Bolzan, Gustavo Roni
AU - Delgado, Cássia Pereira
AU - Aschner, Michael
AU - Orian, Laura
AU - Teixeira Rocha, João Batista
N1 - Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - COVID-19
KW - DFT
KW - docking
KW - organoselenium
KW - protease
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U2 - 10.1002/minf.202100028
DO - 10.1002/minf.202100028
M3 - Article
C2 - 34018687
AN - SCOPUS:85106320420
SN - 1868-1743
VL - 40
JO - Molecular Informatics
JF - Molecular Informatics
IS - 8
M1 - 2100028
ER -