Molecular Docking and Simulation Analysis: Uncover Potential Phytochemical Inhibitors of the SARS-CoV-2 Main Protease

Abstract

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020 has had a profound worldwide impact, with over 773 million confirmed cases reported across multiple countries. To mitigate this crisis, several vaccines and repurposed drugs have been deployed under emergency use authorization. However, concerns remain regarding the side effects and limited efficacy of some repositioned therapeutics. In the search for alternative strategies, computational approaches have identified numerous potential inhibitors of the viral main protease (Mpro), a key enzyme in viral replication. In this study, we compiled a phytochemical library of 2,453 compounds with reported antiviral properties, curated through an extensive literature review. Virtual molecular docking analysis identified five bioactive compounds- theaflavate C, theaflavin-3,3′-O-digallate, amentoflavone, hinokiflavone, and theaflavin-3-gallate-that displayed notably high binding affinities toward SARS-CoV-2 Mpro, with docking scores ranging from –10.1 to –9.7 kcal/mol. These top candidates were subsequently subjected to 20-nanosecond molecular dynamics (MD) simulations using the GROMACS package. Post MD analysis and MM-PB/GBSA calculations indicated that four out of the top five docked compounds exhibit significant stability, flexibility, and favorable binding affinity towards the COVID-19 Mpro (Mpro). Phytochemicals: Theaflavin-3,3-O-digallate, amentoflavone, hinokiflavone and theaflavin3-gallate can be used to design effective antiviral drugs against the SARS- CoV-2.