Virtual Screening and binding mode analysis of selected FDA approved drugs against PLpro target: An effort to identify therapeutics to combat COVID-19

Papain-like protease (PLpro) is one of the most promising targets for anti-SARS-CoV drugs. In this study, a bioactive library of FDA-approved drugs has virtually been screened using a new successful computational pipeline in the framework of the ensemble docking to identify potential binding molecules of PLpro. Based on our protocol, 20 FDA-approved drugs were found to bind the target enzyme with significant affinities and good geometries, suggesting their potential to be utilized against the virus. Our computational studies identified IMATINIB, a well-characterized drug used in the treatment of lymphoblastic and chronic myeloid leukemia, as a potential inhibitor against PLpro. Subsequently, SIMEPREVIR, NALDEMEDINE, TUCATINIB, and some other FDA-approved drugs exhibit great affinities to the PLpro. These drugs are used in the treatment of several diseases such as cancer, schizophrenia, hypertension, hepatitis C, HIV infection, and AIDS showed high affinities in the screening. The high affinity of ligands was rationalized by the newly identified allosteric site named BL2 groove. Occupying this groove may disrupt access to the catalytic site and affect the protein function. The best binding mode and the efficacy of hydrogen bonds and hydrophobic interactions on inhibitory activities of ligands were also disclosed. Furthermore, our studies provide significant molecular insight into PLpro inhibition that could aid in the development of new drugs for COVID-19 treatment.