Reactivity and binding mode of disulfiram, its metabolites, and derivatives in SARS-CoV-2 PL(pro): insights from computational chemistry studies

The papain-like protease (PL(pro)) 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 PL(pro) 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 PL(pro) 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 PL(pro) and should be tested in in vitro and in vivo assays to confirm their antiviral action. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00894-022-05341-2.