Apigenin Derivatives as Promising Norovirus RdRp Inhibitors: Insights from In Silico Docking and Molecular Dynamics Studies.

Abstract

Norovirus is a leading cause of acute gastroenteritis worldwide, yet no approved antivirals currently exist. In this study, we employed in silico approaches to evaluate apigenin derivatives as potential inhibitors of norovirus RNA-dependent RNA polymerase (RdRp). Seventy-three compounds were initially retrieved from the ZINC database, of which 36 satisfied Lipinski's Rule of Five and were advanced for detailed analysis. Pharmacokinetic predictions revealed high intestinal absorption and favorable drug-likeness profiles for most derivatives, with limited central nervous system penetration, desirable for targeting gastrointestinal infections. Molecular docking identified ZINC14636470 (A1) as the top candidate with strong binding affinity (-9.9 kcal/mol) and key hydrogen bond interactions at the RdRp active site. Molecular dynamics simulations confirmed the stability of the A1-RdRp complex (RMSD = 0.20 ± 0.03 nm; Rg = 2.39 ± 0.02 nm). While AMES predictions flagged some derivatives as potentially mutagenic, scaffold optimization may mitigate these risks. Apigenin derivatives, particularly A1, demonstrate promising inhibitory potential against norovirus RdRp, combining favorable pharmacokinetic properties with stable enzyme binding. These findings provide a computational foundation for subsequent in vitro and in vivo validation, supporting the development of natural flavonoid-based scaffolds as antiviral leads against norovirus.