Multi-pronged approaches to the mechanism-based inactivation of aldose reductase by natural coumarins: molecular insights and experimental validation.

In this study, we measured the inhibitory potential of six coumarins against aldose reductase using both computational and experimental approaches. Molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations identified auraptene, marmesin, and isopimpinellin as the most promising inhibitors, with binding affinities of ΔG = -34.88, -29.40, and -20.31 kcal/mol, respectively. ADMET analysis indicated favorable pharmacokinetic properties for all three compounds, including high gastrointestinal absorption and bioavailability. In vitro assays confirmed auraptene as the most potent inhibitor with the lowest IC (1.43 ± 0.14 µM), outperforming quercetin (IC = 2.50 ± 0.31 µM). Marmesin and isopimpinellin showed IC values of 3.80 ± 0.1 µM and 5.71 ± 0.8 µM, respectively. Kinetic studies revealed auraptene as a noncompetitive inhibitor (K = 1.84 µM), isopimpinellin as a competitive inhibitor (K = 1.83 µM), and marmesin as a mixed inhibitor (K = 2.32 µM). These results suggest auraptene and marmesin as potential lead compounds for AR inhibition with strong binding affinities and favorable pharmacokinetic profiles.