Mechanism-based inhibition of aldose reductase by natural xanthones: Computational and experimental insights for diabetic complications

Aldose reductase (AR) plays a pivotal role in the polyol pathway and is a key therapeutic target for preventing diabetic complications. In this study, we employed a multi-disciplinary approach—combining in silico molecular modelling and in vitro enzyme assays—to identify potent AR inhibitors from six naturally occurring xanthone derivatives. Docking, Molecular dynamics simulation, and MM/PBSA calculations revealed that garcinone E, norathyriol, and smeathxanthone A demonstrated the strongest binding affinities and stable interactions with critical residues in the AR binding site. Free energy landscape analysis further highlighted their ability to stabilize AR in low-energy conformational states, reducing enzyme flexibility. ADMET profiling indicated that norathyriol, bellidifolin, and 1-hydroxy-3,5,6,7-tetramethoxyxanthone exhibit favourable pharmacokinetic properties, including high gastrointestinal absorption and compliance with Lipinski’s rule of five, whereas mangiferin displayed poor bioavailability and permeability. In vitro validation confirmed the potent inhibitory activity of garcinone E (IC₅₀ = 4.66 ± 0.21 µM), norathyriol (IC₅₀ = 5.75 ± 0.36 µM), and smeathxanthone A (IC₅₀ = 7.92 ± 1.12 µM), comparable to quercetin (IC₅₀ = 2.46 µM). Enzyme kinetics revealed that garcinone E and smeathxanthone A act as non-competitive inhibitors, while norathyriol shows mixed inhibition, suggesting diverse binding mechanisms that enhance their efficacy. Collectively, these xanthones represent promising oral leads for attenuating diabetic neuropathy, retinopathy, and nephropathy by modulating the polyol pathway. Future work will focus on rational structural optimisation, in vivo validation in diabetic models, and comprehensive pre-clinical safety profiling to progress these compounds toward clinical development.