Revelation of potential antiviral activity of Azadirachta indica against Zika virus protease: An integrated molecular docking and dynamic simulation approach

The Zika virus (ZIKV) is an RNA virus that mostly affects humans and primates and is transmitted via Aedes mosquitoes . The emergence of ZIKV has intensified global health concerns, emphasizing the urgent need for effective antiviral therapies. As a vital enzyme in the replication of ZIKV, the NS2B-NS3 protease offers a promising therapeutic target. This study leverages computer-aided drug design to identify bioactive compounds capable of inhibiting the ZIKV NS2B-NS3 protease, thereby disrupting viral replication. Bioactive compounds from Azadirachta indica were screened through virtual approaches, resulting in six with exceptional docking scores (<-5.5 kcal/mol). Analyses of the physicochemical properties validated the drug-like traits of the IMPHY014854 and IMPHY014908, conveying suitable hydrogen bonding profiles and moderate solubility (Log S: −2.22 to −3.60). Evaluations of pharmacokinetics suggested significant gastrointestinal absorption while exposing no permeability across the blood-brain barrier, thereby reducing interactions with the central nervous system. Toxicity evaluations revealed limited toxic effects, while several bioactive compounds exhibited particular toxicological issues. Molecular dynamics simulations further revealed the stability and interaction dynamics of ZIKV protease-ligand complexes, where the IMPHY014854 and IMPHY014908 exhibited significant residue flexibility, compactness, and solvent accessibility profiles over a 100 ns simulation. Principal component analysis revealed conformational distinctions, while Gibbs's free energy analysis demonstrated greater stability for the ZIKV protease-IMPHY014908 complex. This integrative computational strategy highlights the potential of phytochemicals as the ZIKV protease inhibitors and provides a foundation for developing effective antiviral drugs. Further, in vivo studies must be implemented to validate these findings and advance therapeutic prospects against ZIKV.