Targeting SARS-CoV-2 Main Protease Variants: Investigating the Role of the P132H Mutation in Ligand Binding and the Potential of Withania somnifera Phytochemicals

Mutations in viral proteins, especially at allosteric sites, can profoundly influence therapeutic strategies by altering protein dynamics, stability, and ligand interactions. This study investigates how the P132H mutation in SARS-CoV-2 Main protease (Mpro), an allosteric mutation distal to the catalytic pocket, reshapes the protein’s dynamics and ligand-binding properties. Our findings provide compelling evidence that such allosteric mutations can introduce structural plasticity, altering therapeutic responses and posing both challenges and opportunities for drug design. Phytoconstituents from Withania somnifera emerge as promising candidates, with compounds like Coagulin Q and Withanolide J showing potential to exploit allosteric changes for effective inhibition. By unraveling the interplay between allosteric regulation and protein-ligand dynamics, our work offers an effective framework for understanding mutation-driven structural adaptations in viral proteins. Here, the binding dynamics of Withania somnifera phytoconstituents with both wild-type (WT) and P132H mutant (MT) Mpro was explored using molecular docking, 10.2 µs MD simulations, MM-GBSA energy decomposition, PCA, DCCM analysis, Global Community Analysis, residue-residue interaction network analysis and solvent-accessible surface area (SASA) analysis. The potential of phytoconstituents from Withania somnifera as antiviral agents offers promising avenues for therapeutic development against SARS-CoV-2 variants and other rapidly evolving pathogens. This study emphasizes the importance of integrating allosteric mechanisms into antiviral design strategies, presenting insights that could inform the development of therapeutics against not only SARS-CoV-2 but also other rapidly mutating pathogens.