Screening for Potential Traditional Herbal Inhibitors Against 3-Chymotrypsin- like Main Protease (3CLpro) from Four Different Coronaviruses: An in silico Approach

Abstract

Background: The recent outbreak of the COVID-19 pandemic has raised a global health concern due to the unavailability of any vaccines or drugs. The repurposing of traditional herbs with broad-spectrum anti-viral activity can be explored to control or prevent a pandemic. Objective: The 3-chymotrypsin-like main protease (3CLpro), also referred to as the “Achilles’ heel” of the coronaviruses (CoVs), is highly conserved among CoVs and is a potential drug target. 3CLpro is essential for the virus’ life cycle. The objective of the study was to screen and identify broad- -spectrum natural phytoconstituents against the conserved active site and substrate-binding site of 3CLpro of HCoVs. Methods: Herein, we applied the computational strategy based on molecular docking to identify potential phytoconstituents for the non-covalent inhibition of the main protease 3CLpro from four different CoVs, namely, SARS-CoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Results: Our study shows that natural phytoconstituents in Triphala (a blend of Emblica officinalis fruit, Terminalia bellerica fruit, and Terminalia chebula fruit), namely chebulagic acid, chebulinic acid, and elagic acid, exhibited the highest binding affinity and lowest dissociation constants (Ki), against the conserved 3CLpro main protease of SARSCoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Besides, phytoconstituents of other herbs like Withania somnifera, Glycyrrhiza glabra, Hyssopus officinalis, Camellia sinensis, Prunella vulgaris, and Ocimum sanctum also showed good binding affinity and lower Ki against the active site of 3CLpro. The top-ranking phytoconstituents’ binding interactions clearly showed strong and stable interactions with amino acid residues in the catalytic dyad (CYS-HIS) and substrate-binding pocket of the 3CLpro main proteases. Conclusion: This study provides a valuable scaffold for repurposing traditional herbs with anti-- CoV activity to combat SARS-CoV-2 and other HCoVs until the discovery of new therapies.