Natural‐Product‐Based Discovery of Zika Virus NS5‐RdRp Inhibitors via Structure‐Based Design and Quantum Reactivity Filters

In this study, we employed an in silico drug design approach to identify novel natural inhibitors targeting the Zika virus RNA‐dependent RNA polymerase (NS5‐RdRp). A four‐feature energy‐optimized pharmacophore (AARR) model was derived from the sofosbuvir–NS5 complex and validated using enrichment analysis. Virtual screening of a large natural compound database, followed by molecular docking, yielded 82 hits with high binding affinities (−10.59 to −8.00 kcal/mol). Nine candidates were shortlisted based on favorable toxicological profiles, and two compounds (L04 and L05) demonstrated optimal pharmacokinetic properties in ADME analysis. Molecular dynamics simulations further confirmed the stability of compound L04 within the NS5 active site, maintaining key interactions with catalytic residues. These findings underscore the potential of pharmacophore‐based virtual screening combined with molecular simulations as an effective strategy for discovering novel antiviral agents against the Zika virus.