Abstract
The spread of SARS-CoV-2 has affected human health globally. Hence, it is necessary to rapidly find the drug-candidates that can be used to treat the infection. Since the main protease (Mpro) is the key protein in the virus’s life cycle, Mpro is served as one of the critical targets of antiviral treatment. We employed virtual screening tools to search for new inhibitors to accelerate the drug discovery process. The hit compounds were subsequently docked into the active site of SARS-CoV-2 main protease and ranked by their binding energy. Furthermore, in-silico ADME studies were performed to probe for adoption with the standard ranges. Finally, molecular dynamics simulations were applied to study the protein-drug complex’s fluctuation over time in an aqueous medium. This study indicates that the interaction energy of the top ten retrieved compounds with COVID-19 main protease is much higher than the interaction energy of some currently in use protease drugs such as ML188, nelfinavir, lopinavir, ritonavir, and α-ketoamide. Among the discovered compounds, Pubchem44326934 showed druglike properties and was further analyzed by MD and MM/PBSA approaches. Besides, the constant binding free energy over MD trajectories suggests a probable drug possessing antiviral properties. MD simulations demonstrate that GLU166 and GLN189 are the most important residues of Mpro, which interact with inhibitors.
【저자키워드】 COVID-19, main protease, molecular docking, Virtual screening, Molecular dynamics simulation, ADME studies, 【초록키워드】 SARS-CoV-2, Drug discovery, Ritonavir, Infection, drug, Antiviral treatment, protease, virus, binding free energy, inhibitors, SARS-CoV-2 main protease, ADME, MD simulation, binding energy, MPro, Spread, Protein, Health, trajectory, target, in-silico, inhibitor, Critical, compounds, MM/PBSA, Interaction, approaches, medium, complex, residue, Compound, antiviral properties, treat, probe, fluctuation, analyzed, performed, affected, applied, can be used, indicate, much higher, accelerate, docked, retrieved, with COVID-19, 【제목키워드】 Protease inhibitor, Coronavirus 2019,