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.
【초록키워드】 COVID-19, Drug repurposing, SARS-CoV-2, pandemic, drug design, drugs, molecular docking, Virtual screening, drug, molecular dynamics, antiviral activity, computer-aided drug design, database, MD simulations, binding affinity, MD simulation, binding energy, Molecular dynamics simulation, Viral pneumonia, Cell culture, antiviral therapeutics, experiment, molecular, medication, inhibitor, Interaction, Analysis, bemcentinib, active site, Nilotinib, strength, indication, 6LU7, M pro, sequence, His41, drug candidate, Glu166, high accuracy, researcher, independent, Drug Bank, predicted, Partial, significantly, was performed, suggested, subset, were measured, the binding affinity, Bank, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, repurposing, drug, insight, Potential,