Identifying and Evaluating Flavonoids as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro/3CL) Through Docking and Molecular Dynamics

Abstract

Although the acute phase of the SARS-CoV-2 pandemic has subsided, the continued emergence of viral variants underscores the need for structurally diverse antiviral inhibitors. In this study, molecular docking followed by molecular dynamics (300 ns) simulations and binding free energy calculations using the Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) method were employed to evaluate substituted flavonoids derived from Taraxacum officinale and Urtica dioica as potential inhibitors of the SARS-CoV-2 main protease (Mpro/3CLpro). Docking analysis identified several derivatives with favorable binding scores; however, dynamic refinement revealed differential stability among the ligand–protein complexes. Among the evaluated compounds, the luteolin derivative LND-17 showed the most consistent performance, exhibiting binding free energy estimates approaching those obtained for the reference inhibitors nirmatrelvir and ensitrelvir, sustained catalytic pocket occupancy, and energetic contributions involving the catalytic dyad (His41 and Cys145). Additional derivatives, including LNG-04, QND-07, and QNG-20, showed moderate stabilization but lower overall consistency. These findings highlight glycosylated flavonoids as promising scaffolds for future structure-based optimization and provide structural insights to guide experimental validation.