Abstract
The main protease (Mpro) of SARS-CoV-2 is a current target for the inhibition of viral replication. Through a combined Docking and Density Functional Theory (DFT) approach, we investigated in-silico the molecular mechanism by which ebselen (IUPAC: 2-phenyl-1,2-benzoselenazol-3-one), the most famous and pharmacologically active organoselenide, inhibits Mpro. For the first time, we report on a mechanistic investigation in an enzyme for the formation of the covalent -S-Se- bond between ebselen and a key enzymatic cysteine. The results highlight the strengths and weaknesses of ebselen and provide hints for a rational drug design of bioorganic selenium-based inhibitors.
Highlights
The main protease (Mpro ) and papain-like protease (PLpro ) of SARS-CoV-2 are suitable targets for the pharmacological action against its viral replication [1]
Sancineto et al [15] reported interesting results indicating that the inhibitory capacity of organoselenium compounds towards Mpro is greatly reduced upon dimerization to diselenides, and Ma et al recently demonstrated that, under reducing conditions, i.e., in the presence of 1,4-dithiothreitol (DTT) and/or glutathione (GSH), EbSe is not able to effectively inhibit SARS-CoV-2 Mpro as well as a panel of other Cys proteases [16,17]
While conformational freedom of the backbone might help in stabilizing an Ion Pair, which was located in another Mpro mechanistic investigation [50], our results suggest that the cysteinate attack to the Se-N bond occurs with a very low, if any, activation energy
Summary
The main protease (Mpro ) and papain-like protease (PLpro ) of SARS-CoV-2 are suitable targets for the pharmacological action against its viral replication [1]. Both enzymes are Cysteine (Cys) proteases [2,3], and in the case of Mpro , the mechanism closely resembles the well-studied mechanism of Serine protease. Sancineto et al [15] reported interesting results indicating that the inhibitory capacity of organoselenium compounds towards Mpro is greatly reduced upon dimerization to diselenides, and Ma et al recently demonstrated that, under reducing conditions, i.e., in the presence of 1,4-dithiothreitol (DTT) and/or glutathione (GSH), EbSe is not able to effectively inhibit SARS-CoV-2 Mpro as well as a panel of other Cys proteases [16,17]. Further investigation is important to understand the true antiviral potential of organoselenium compounds, starting from the chemical mechanism, and progressively moving to realistic biological conditions
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