ABSTRACTDengue (DENV) and Zika virus (ZIKV), transmitted by Aedes mosquitoes, pose significant public health challenges. Effective treatments for these viruses remain elusive, highlighting the urgent need for new efficient antiviral therapies. This study explores prodigiosin, a microbial tripyrrole pigment, as an antiviral agent against both DENV and ZIKV employing advanced analytical approaches which integrate molecular docking, CASTp 3.0 validation and molecular dynamics (MD) simulations providing insights into molecular interactions at an atomic level. Prodigiosin exhibited favourable drug‐likeness properties, meeting Lipinski's rule of five and demonstrating optimal physicochemical and pharmacokinetic characteristics according to Ghose's, Veber's, Egan's and Muegge's filters, essential for oral bioavailability. Absorption, Distribution, Metabolism, Excretion, and Toxicity profiling indicated high intestinal absorption, minimal risk for drug‐drug interactions and a low toxicity profile, with no AMES toxicity, hepatotoxicity, or skin sensitization. Molecular docking revealed prodigiosin's strong binding affinities to NS5 methyltransferases of both DENV (−7.6 kcal/mol) and ZIKV (−7.7 kcal/mol) viruses, suggesting potential disruption of viral replication. Notably, prodigiosin's binding affinities were comparable to ribavirin‐5'‐triphosphate and chloroquine, known inhibitors of DENV and ZIKV, respectively. MD simulations confirmed stable and specific interactions with prodigiosin with low root‐mean‐square deviation values. Additional analyses, including root‐mean‐square fluctuation, radius of gyration and solvent‐accessible surface area, indicated compact and stable complexes. These multi‐parametric in‐silico analytical strategies provide a novel perspective of prodigiosin as an antiviral agent, demonstrating its drug interactions at the molecular level. These promising results suggest that prodigiosin could serve as a broad‐spectrum antiviral agent against both DENV and ZIKV, warranting further experimental validation for therapeutic development against flaviviral infections.
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