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