Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

Abstract

Background: The emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. Rapid development of new drug molecules is the need of hour to fight COVID-19. However, the conventional approaches of drug development are time consuming and expensive. Here, we have adopted a computational approach to identify lead molecules from nature. Ligands from natural compounds library available at Selleck Inc (L1400) have been screened for their ability to bind and inhibit the main protease (3CLpro) of SARS-CoV-2. Methods: The natural compounds library of Selleck Inc. (Catalog No. L1400) were retrieved from www.selleckchem.com. It contains 2230 compounds in sdf format, curated from natural sources. Prior to molecular docking, all the ligands were prepared by adding hydrogen atoms and merging them with non-polar hydrogen atoms. Gasteiger partial charges were added, rotatable bonds were defined, and the energies were minimized using MMFF94 forcefield (11,12). The three-dimensional coordinates of the main protease (Mpro), also known as 3C-like protein (3CLpro), was downloaded from the protein databank available at https://www.rcsb.org/structure/6LU7. The structure was solved to a resolution of 2.16 Å and is bound with a peptide-like inhibitor (N3)(8). The structure of target was prepared for molecular docking by adding hydrogen atoms, Kollman united atom type charges and solvation parameters using AutoDock Tool (ADT) (13). Results: We found that Kaempferol, Quercetin, and Rutin were bound at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin (~106 M-1) was much higher than Chloroquine (~103 M-1) and Hydroxychloroquine (~104 M-1), and the reference drug Remdesivir (~105 M-1). Conclusion: The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable/higher potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.