Diphenyl Diselenide and SARS-CoV-2: in silico Exploration of the Mechanisms of Inhibition of Main Protease (M^pro) and Papain-like Protease (PL^pro)

Abstract

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.

Solvent effect on the 77Se NMR chemical shifts of diphenyl diselenides

“…Moreover, diphenyl diselenide is a tricky compound when it comes to chemical shift prediction, since the softness of the Se–Se bond and the free rotation of the phenyl rings lead to a plethora of accessible structures in solution, 80 and, as more recently reported, also in a protein environment. 81 During the NMR experiment, the chemical shift of all these structures is averaged out. As a first approximation, we attempted to take this aspect into account in our calculation considering two different conformers identified in gas phase calculations in previous studies according to the different Φ ( C–C–Se–Se) dihedrals involving the diselenide bridge and the C–C bond of phenyl (Scheme 1).…”

New insights in the mechanism of the SARS-CoV-2 Mpro inhibition by benzisoselenazolones and diselenides

“…This is the case of compound 8, which is still able to inhibit M pro , but thought a non-covalent mechanism as recently proposed by Orian and Rocha. 42 HRMS analysis performed under reducing conditions (for the presence of DTT, see SI) evidenced that both selenazolones and diselenides bind covalently the M pro , but not in the same manner and not selectively. The mass of apo M pro is ~ 33.8 kDa, in line with previous observations.…”

Reactivity of Palladium(II)-η3-Allyl Complexes with Chalcogenolates: A Density Functional Study of Their Antitumor Implications

“…Thus, the reactivity of these complexes with thiolates and selenolates should be evaluated to obtain a molecular understanding of the chemical mechanisms at the basis of protein inhibition. Model molecular studies have been used in different contexts to rationalize protein inhibition phenomena involving chalcogenol residues as substrates, i.e., Cys and Sec, − as well as other enzyme residues, also in enzymatic clusters. , Moreover, the use of simplified models allows elucidation of the chemical mechanistic details with accuracy, eventually ruling out intrinsically disfavored paths and identifying key elementary reactions for protein inhibition.…”