A Potential Molecular Inhibitor of the SARS-COV-2 Main Protease Obtained by Virtual Screening

Abstract SARS-CoV-2 has been out breaking around the world for more than three years and continues to evolve variants, which has become a major global health threat. Main protease (M pro , also called 3CL pro ) plays a key role in viral replication and proliferation, making it an attractive drug target. Here, we have identified novel potential inhibitor of M pro by applying a virtual screening of hundreds Nilotinib structure-like compounds we designed and synthesized. The screened compounds were followed for the SP docking, XP docking, MM-GBSA analysis, IFD docking, MD simulation, ADME/T prediction and then enzymatic assay in vitro . We finally identified compound V291 as a potential SARS-COV-2 M pro inhibitor with high docking affinity and enzyme inhibitory activity. Moreover, the docking results indicate that His41 is a favorable amino acid for pi-pi inter-actions, while Glu166 can participate in salt bridge formation with protonated primary or secondary amines in the screened molecules. Thus, compounds reported here are capable of engaging the key amino acids His41 and Glu166 in ligand-receptor interactions. Pharmacophore analysis further validates this assertion.