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

## TL;DR

This study identifies plant-based flavonoids that may bind to GLUT9 and have antioxidant properties, potentially offering new treatments for hyperuricemia.

## Contribution

The study introduces a computational and experimental approach to identify flavonoids as potential GLUT9 binders with antioxidant activity.

## Key findings

- Eight flavonoids showed favorable binding affinities to GLUT9, with EGCG having the highest at −9.10 kcal/mol.
- EGCG demonstrated superior antioxidant activity compared to ascorbic acid with a DPPH IC50 of 3.28 μM.
- MD simulations confirmed structural stability of the flavonoid-GLUT9 complexes over 100 ns.

## 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 μM) 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.