Abstract
COVID-19, an acute viral pneumonia, has emerged as a devastating pandemic. Drug repurposing allows researchers to find different indications of FDA-approved or investigational drugs. In this current study, a sequence of pharmacophore and molecular modeling-based screening against COVID-19 M(pro) (PDB: 6LU7) suggested a subset of drugs, from the Drug Bank database, which may have antiviral activity. A total of 44 out of 8823 of the most promising virtual hits from the Drug Bank were subjected to molecular dynamics simulation experiments to explore the strength of their interactions with the SARS-CoV-2 M(pro) active site. MD findings point toward three drugs (DB04020, DB12411, and DB11779) with very low relative free energies for SARS-CoV-2 M(pro) with interactions at His41 and Met49. MD simulations identified an additional interaction with Glu166, which enhanced the binding affinity significantly. Therefore, Glu166 could be an interesting target for structure-based drug design. Quantitative structural-activity relationship analysis was performed on the 44 most promising hits from molecular docking-based virtual screening. Partial least square regression accurately predicted the values of independent drug candidates' binding energy with impressively high accuracy. Finally, the EC(50) and CC(50) of 10 drug candidates were measured against SARS-CoV-2 in cell culture. Nilotinib and bemcentinib had EC(50) values of 2.6 and 1.1 μM, respectively. In summary, the results of our computer-aided drug design provide a roadmap for rational drug design of M(pro) inhibitors and the discovery of certified medications as COVID-19 antiviral therapeutics.