Natural Metabolites from Clinacanthus nutans as Promising SARS-CoV-2 Main Protease Inhibitors: Insights from Molecular Docking and Dynamics Simulations

Structure-based drug design against SARS-CoV-2 main protease (Mpro) was enabled by the availability of its crystal structure (PDB ID: 6LU7). In this study, metabolites from Clinacanthus nutans were computationally evaluated as potential Mpro inhibitors using validated molecular docking and molecular dynamics (MD) approaches. Native ligand re-docking produced an RMSD of 1.329 Å, confirming the reliability of the docking setup. Among the tested compounds, vitexin demonstrated a favorable binding affinity in docking analysis, indicating its potential for interaction within the active site of Mpro. However, further evaluation using 100 ns MD simulations and MM/PBSA free energy calculations revealed that, although the vitexin–Mpro complex remained relatively stable, the native ligand exhibited superior thermodynamic stability and binding free energy. Overall, vitexin shows promising binding characteristics as a natural compound targeting Mpro, but it does not surpass the native ligand in terms of overall binding stability. These findings suggest that vitexin may serve as a potential lead compound, warranting further optimization and experimental validation.