Integrating the knowledge of traditional medicine to identify potential anti-viral drug against Human Norovirus (HNV); a molecular docking, simulation and network pharmacology analysis

• First-of-its-kind integration of traditional medicinal phytocompounds with advanced computational methods to target Human Norovirus (HNV). • Discovery of three potent natural RdRp inhibitors (Raucaffricine, Camptothecin, Strictosidine) outperforming Favipiravir. • Dual profiling of binding strength and kinetics using MM-GBSA and metadynamics—highlighting Camptothecin’s longer residence time. • Network pharmacology analysis identifies TRIM29 as a key immune regulator in HNV pathogenesis. • Bridges the gap between CAM medicine with modern drug discovery , promoting evidence-based use of traditional systems in antiviral therapy. Human Norovirus (HNV) is an emerging public health threat with no approved antivirals. There is a need to explore novel therapeutic leads, particularly from phytochemicals with CAM and other branches of medicine. This study aimed to identify potential phytochemical inhibitors of the HNV RNA-dependent RNA polymerase (RdRp), a key enzyme in viral replication. This study aimed to identify potential phytochemical inhibitors of the HNV RNA-dependent RNA polymerase (RdRp), a key enzyme in viral replication. Fifty-one phytochemicals, selected from literature based on reported antiviral or ethnomedicinal evidences, were retrieved from PubChem and docked against the RdRp protein (PDB ID: 4LQ3) using AutoDock Vina. Drug-likeness was assessed via Swiss ADME. Subsequently, all-atom molecular dynamics simulations (500 ns) were conducted to investigate the stability of the ligand–protein complexes. Binding free energy was quantified using MM-GBSA, and dissociation kinetics were explored through metadynamics simulations. Strictosamide, Camptothecin, and Raucaffricine outperformed both the co-crystallized ligand and Favipiravir in docking. ADME analysis showed that Camptothecin and Raucaffricine possessed favourable drug-likeness and high gastrointestinal absorption, with no Lipinski’s or Veber’s violations. Dynamics simulations revealed that Camptothecin provided strong conformational stabilization of RdRp, whereas Raucaffricine displayed greater flexibility. MM-GBSA highlighted Raucaffricine’s superior thermodynamic binding (ΔG_bind = –189.6 kcal/mol), while metadynamics showed Camptothecin’s higher dissociation energy barrier (ΔG_off = 14.5 kcal/mol), indicating longer target residence time. This integrative computational study identifies Camptothecin and Raucaffricine as promising anti-viral candidates to be considered against HNV. While Raucaffricine demonstrated stronger thermodynamic affinity, Camptothecin exhibited superior kinetic stability, which may enhance pharmacological efficacy.