In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

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.

Case Study of High-Throughput Drug Screening and Remote Data Collection for SARS-CoV-2 Main Protease by Using Serial Femtosecond X-ray Crystallography

“…Ebselen has been proven to be a potent inhibitor of SARS-CoV-2 Mpro through HTS studies [48,49]. Not only in silico studies [50,51] but also in crystallographic studies [52] it has been shown that ebselen can bind to the relevant region of the Mpro. Accordingly, studies on the effect of ebselen on Mpro crystals support the precipitation we observed in our Mpro-ebselen sample, and hence the potential inhibitor effect of ebselen on SARS-CoV-2.…”

Potential of Marine Terpenoids against SARS-CoV-2: An In Silico Drug Development Approach

“…In the meantime, worldwide laboratories share a massive amount of genomic information, which is most difficult to analyze without bioinformatics tools. Additionally, project many potential drugs and natural products against SARS-CoV-2 with the CADD platform [ 18 , 79 , 98 , 99 , 100 ]. At present, several tools and databases of bioinformatics are available for gene analysis to vaccine/drug development.…”

“…From SAR analysis, cyclodecene (C 10 H 18 ), cyclohexene oxide (C 6 H 10 O), and γ-butyrolactone or dihydrofuran-2(3H)-one (C 4 H 6 O 2 ) with chlorine in each in all three structures. Indeed, the presence of two methyl butyrate, one methyl acetate with a methyl−like group attachment project many potential drugs and natural products against SARS-CoV-2 with the CADD platform [18,79,[98][99][100]. At present, several tools and databases of bioinformatics are available for gene analysis to vaccine/drug development.…”

Selenium-Catalyzed Reduction of Hydroperoxides in Chemistry and Biology

“…The mechanisms of these nucleophilic substitutions have been tackled in detail by several authors [25,[75][76][77][78]. Among the examples reported in literature, it is worth to mention the antidepressant lithium-like potential of ebselen as inositol monophosphatase inhibitor [79,80], as disruptor of protein Zn fingers [81,82], and, more recently, ebselen has been repurposed as SARS Cov 2 M pro inhibitor [83][84][85][86], justifying its antiviral activity measured in vitro.…”