Computational analysis of the interactions between Ebselen and derivatives with the active site of the main protease from SARS-CoV-2.

The main protease (Mpro) of the novel coronavirus SARS-CoV-2 is a key target for developing antiviral drugs. Ebselen (EbSe) is a selenium-containing compound that has been shown to inhibit Mpro in vitro by forming a covalent bond with the cysteine (Cys) residue in the active site of the enzyme. However, EbSe can also bind to other proteins, like albumin, and low molecular weight compounds that have free thiol groups, such as Cys and glutathione (GSH), which may affect its availability and activity. In this study, we analyzed the Mpro interaction with EbSe, its analogues, and its metabolites with Cys, GSH, and albumin by molecular docking. We also simulated the electronic structure of the generated molecules by density functional theory (DFT) and explored the stability of EbSe and one of its best derivatives, EbSe-2,5-MeClPh, in the catalytic pocket of Mpro through covalent docking and molecular dynamics. Our results show that EbSe and its analogues bound to GSH/albumin have larger distance between the selenium atom of the ligands and the sulfur atom of Cys145 of Mpro than the other compounds. This suggests that EbSe and its GSH/albumin-analogues may have less affinity for the active site of Mpro. EbSe-2,5-MeClPh was found one of the best molecules, and in molecular dynamics simulations, it showed to undergo more conformational changes in the active site of Mpro, in relation to EbSe, which remained stable in the catalytic pocket. Moreover, this study also reveals that all compounds have the potential to interact closely with the active site of Mpro, providing us with a concept of which derivatives may be promising for in vitro analysis in the future. We propose that these compounds are potential covalent inhibitors of Mpro and that organoselenium compounds are molecules that should be studied for their antiviral properties.

Diphenyl Diselenide and SARS-CoV-2: in silico Exploration of the Mechanisms of Inhibition of Main Protease (Mpro) and Papain-like Protease (PLpro).

The SARS-CoV-2 pandemic has prompted global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro) and the papain-like protease (PLpro) are essential for viral replication and are key targets for therapeutic development. In this work, we investigate the mechanisms of SARS-CoV-2 inhibition by diphenyl diselenide (PhSe)2 which is an archetypal model of diselenides and a renowned potential therapeutic agent. The in vitro inhibitory concentration of (PhSe)2 against SARS-CoV-2 in Vero E6 cells falls in the low micromolar range. Molecular dynamics (MD) simulations and density functional theory (DFT) calculations [level of theory: SMD-B3LYP-D3(BJ)/6-311G(d,p), cc-pVTZ] are used to inspect non-covalent inhibition modes of both proteases via π-stacking and the mechanism of covalent (PhSe)2 + Mpro product formation involving the catalytic residue C145, respectively. The in vitro CC50 (24.61 µM) and EC50 (2.39 µM) data indicate that (PhSe)2 is a good inhibitor of the SARS-CoV-2 virus replication in a cell culture model. The in silico findings indicate potential mechanisms of proteases' inhibition by (PhSe)2; in particular, the results of the covalent inhibition here discussed for Mpro, whose thermodynamics is approximatively isoergonic, prompt further investigation in the design of antiviral organodiselenides.

Reactivity and binding mode of disulfiram, its metabolites, and derivatives in SARS-CoV-2 PLpro: insights from computational chemistry studies.

The papain-like protease (PLpro) from SARS-CoV-2 is an important target for the development of antivirals against COVID-19. The safe drug disulfiram (DSF) presents antiviral activity inhibiting PLpro in vitro, and it is under clinical trial studies, indicating to be a promising anti-COVID-19 drug. In this work, we aimed to understand the mechanism of PLpro inhibition by DSF and verify if DSF metabolites and derivatives could be potential inhibitors too. Molecular docking, DFT, and ADMET techniques were applied. The carbamoylation of the active site cysteine residue by DSF metabolite (DETC-MeSO) is kinetically and thermodynamically favorable (ΔG‡ = 3.15 and ΔG = - 12.10 kcal mol-1, respectively). Our results strongly suggest that the sulfoxide metabolites from DSF are promising covalent inhibitors of PLpro and should be tested in in vitro and in vivo assays to confirm their antiviral action.

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

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.