Structure-based computational screening and molecular dynamics reveal potential inhibitors of Norovirus VP1 and RdRp Proteins: an in-silico study

Abstract

Abstract Norovirus is a major enteric pathogen with pandemic potential and disproportionately high mortality in low-income countries, particularly among young children. Despite its global health burden, no approved vaccine or specific antiviral therapy is currently available. In this study, we targeted two key viral proteins, viral protein 1 (VP1) and RNA-dependent RNA polymerase (RdRp). The workflow included protein modeling, structural stability assessment, molecular docking, molecular dynamics (MD) simulations, non-covalent interaction (NCI) analysis, protein contact atlas evaluation, and pharmacokinetic (ADME-Tox) profiling. Molecular docking results indicated strong binding affinities of selected phytochemicals—Zingiberol, Cardeonolide, Boeravinone B, β-Elemene, and Fisetin—toward both VP1 and RdRp, with binding energies ranging from − 7.8 to − 9.4 kcal/mol. MD simulations further demonstrated the structural stability of protein–ligand complexes, with stable RMSD values (~ 0.3 nm for RdRp and 0.3–0.5 nm for VP1) and only minor transient fluctuations observed in VP1. RMSF analysis revealed localized flexibility, while radius of gyration, hydrogen bonding patterns, and solvent-accessible surface area collectively confirmed overall conformational stability throughout the simulation period. Complementary protein contact atlas and NCI analyses supported the persistence and robustness of protein–ligand interactions, showing comparable or improved stability relative to reference antivirals ribavirin and nitazoxanide. Additionally, all selected compounds exhibited favorable drug-likeness and acceptable ADME-Tox properties. Collectively, these findings suggest that the identified phytochemicals may serve as promising antiviral candidates against norovirus, although further validation through in vitro and in vivo studies is required.