Identification and mechanistic study of piceatannol as a natural xanthine oxidase inhibitor

Natural Xanthine oxidase (XOD) inhibitors represent promising therapeutic agents for hyperuricemia (HUA) treatment due to their potent efficacy and favorable safety profiles. This study involved the construction of a comprehensive database of 315 XOD inhibitors and development of 28 machine learning-based QSAR models. The ChemoPy light gradient boosting machine model exhibited the best performance (AUC = 0.9371 and MCC = 0.7423). This model identified three potential XOD inhibitors from the FooDB database: daphnetin, 7-hydroxycoumarin, and piceatannol. Molecular docking and dynamics simulations revealed favorable interactions, with piceatannol showing a remarkable stability through hydrogen bonding and hydrophobic interactions. ADME predictions suggested that all three compounds possess desirable drug-like properties and safety characteristics. Subsequent in vitro enzyme inhibition assays validated computational predictions, with piceatannol exhibiting the strongest inhibitory activity (IC 50  = 8.80 ± 0.05 μM). Multispectroscopic analyses revealed that piceatannol–XOD binding was predominantly mediated by hydrogen bonding and van der Waals forces, which induced conformational changes characterized by decreased α-helical content and increased proportions of β-sheets, β-turns, and random coils. This study presents an efficient strategy for the identification of natural XOD inhibitors, elucidates the molecular mechanism of piceatannol-mediated XOD inhibition, and establishes a foundation for its therapeutic application in HUA treatment.