In Silico Analysis of Peptide-Based Derivatives Containing Bifunctional Warheads Engaging Prime and Non-Prime Subsites to Covalent Binding SARS-CoV-2 Main Protease (Mpro)

Despite the progress of therapeutic approaches for treating COVID-19 infection, interest in developing effective antiviral agents is still high, due to possibility insurgence viable SARS-CoV-2-resistant strains. Accordingly, this article, we describe a computational protocol identifying possible SARS-CoV-2 Mpro covalent inhibitors. Combining several silico techniques, evaluated potential peptide-based scaffold with different warheads as significant alternative nitriles and aldehyde electrophilic groups. We rationally designed four inhibitors containing difluorstatone Michael acceptor warheads. In analysis, based on molecular docking, dynamics simulation, FEP, indicated that conceived compounds could act investigated can be used designing against serine or cysteine proteases such Mpro. Our work enriches knowledge Mpro, providing novel strategy its inhibition, paving way development antivirals.