Targeting norovirus RdRp: A computational study on the inhibitory potential of ursolic acid and apigenin-7-O-glucoside.

Objective: Norovirus is a highly contagious pathogen responsible for significant global morbidity and mortality due to severe gastrointestinal illnesses, particularly in settings such as schools, hospitals, and cruise ships. Despite its impact on public health, no effective antiviral treatments or vaccines are currently available. This study seeks to identify natural compounds with inhibitory potential against the Norovirus RNA-dependent RNA polymerase (RdRp), an essential enzyme in viral replication. By focusing on phytochemicals, the research aims to propose novel, safe, and effective antiviral agents that could serve as alternatives to synthetic drugs. Methods: A comprehensive in silico approach was employed to screen and evaluate potential inhibitors of Norovirus RdRp. Candidate compounds were first assessed through pharmacokinetic (ADMET) analysis to evaluate their absorption, distribution, metabolism, excretion, and toxicity profiles, ensuring drug-likeness and safety. Toxicological profiling further confirmed the absence of harmful effects in the selected compounds. Molecular docking studies were performed to predict the binding affinities of natural compounds with the RdRp protein (PDB ID: 3ur0), identifying those with the strongest interactions. Molecular dynamics (MD) simulations were then conducted to assess the dynamic stability of the protein-ligand complexes under physiological conditions. Finally, MM-GBSA binding free energy calculations were used to quantitatively validate the strength and stability of the interactions between the compounds and the target protein. Results: The study identified two lead compounds, Ursolic Acid (CID_64945) and Apigenin-7-O-glucoside (CID_5280704), as potential inhibitors of Norovirus RdRp. Molecular docking studies revealed strong binding affinities, with Ursolic Acid showing a binding score of -8.8 kcal/mol and Apigenin-7-O-glucoside displaying a score of -8.7 kcal/mol. Pharmacokinetic and toxicological evaluations confirmed that both compounds exhibit excellent ADMET profiles, demonstrating favorable absorption, metabolic stability, and minimal toxicity, making them suitable for drug development. Molecular dynamics simulations validated the stability of interactions between the RdRp protein and the two lead compounds over time, with the protein-ligand complexes maintaining consistent and robust interactions throughout the simulation period. MM-GBSA calculations further supported the efficacy of these compounds, as they demonstrated stable and energetically favorable binding to the target protein. Both Ursolic Acid and Apigenin-7-O-glucoside are phytochemicals found in commonly available plants such as rosemary and holy basil, enhancing their accessibility and feasibility for therapeutic use. Conclusion: This study identifies Ursolic Acid and Apigenin-7-O-glucoside as promising natural inhibitors of Norovirus RdRp, showing strong binding, stable interactions, and favorable safety profiles. As plant-derived compounds, they offer a sustainable, cost-effective approach for developing antiviral therapies, warranting further experimental validation.