Structure-Based Virtual Screening of Plant-Derived Flavonoids as Putative GLUT9 Binders with Antioxidant Properties

Abstract

Hyperuricemia affects approximately 20% of the global adult population and serves as the primary etiological factor for gout. Glucose transporter 9 (GLUT9) plays a critical role in renal urate reabsorption, representing a promising therapeutic target for hyperuricemia treatment. This study employed an integrated computational and experimental approach to identify novel flavonoid-based putative GLUT9 binders, combining molecular docking, molecular dynamics (MD) simulations, ADMET prediction, antioxidant evaluation, and density functional theory (DFT) calculations. Eight structurally diverse flavonoids were docked against the human GLUT9 cryo-EM structure, and antioxidant activities were assessed using DPPH, ABTS, and FRAP assays. All tested flavonoids exhibited favorable binding affinities ranging from -7.67 to -9.10 kcal/mol. Epigallocatechin gallate (EGCG) demonstrated the highest binding affinity (-9.10 kcal/mol) with an extensive hydrogen bonding network, while chrysin exhibited the second-highest affinity (-8.35 kcal/mol) with favorable drug-like properties. MD simulations over 100 ns confirmed the structural stability of the complexes. EGCG displayed exceptional antioxidant capacity (DPPH IC50 = 3.28 mu M) superior to ascorbic acid, whereas chrysin showed lower radical scavenging activity despite favorable GLUT9 binding. DFT calculations revealed that higher HOMO energies correlated with enhanced antioxidant activity. These findings suggest that EGCG and chrysin exhibit favorable GLUT9 binding profiles, warranting further functional and pharmacokinetic optimization.