Inhibition mechanism of α-glucosidase by three geranylated compounds: Kinetic, spectroscopic and molecular docking

alpha-Glucosidase inhibitors can effectively control postprandial hyperglycemia and play a crucial role in treating type II diabetes. Geranylated compounds have been demonstrated to have strong alpha-glucosidase inhibitory activity, while their interaction mechanism was still unclear. In this study, we investigated the inhibition mechanisms of three structurally different geranylated compounds with significant alpha-glucosidase inhibition (puerarol, 8-geranyl-7, 3 '-dihydroxy-4 '-methoxyisoflavone, and xanthoangelol) separated from Pueraria lobata. The IC50 values of these compounds were 6.14 +/- 0.20, 2.35 +/- 0.02, and 1.98 +/- 0.07 mu M, respectively. It was found that puerarol acted as a non-competitive inhibitor, while 8-geranyl-7, 3 '-dihydroxy-4 '-methoxyisoflavone and xanthoangelol acted as un-competitive inhibitors. Fluorescence and circular dichroism data indicated that all three geranylated compounds statically quenched the fluorescence of alpha-glucosidase, and bound to alpha-glucosidase through a single binding site, inducing rearrangement of alpha-glucosidase and leading to conformational changes. Thermodynamic analysis and molecular docking revealed that puerarol interacted with alpha-glucosidase through hydrogen bonds and van der Waals forces, while the other two compounds primarily interacted through hydrophobic forces. This study elucidated the binding mechanism between three different structural geranylated compounds and alpha-glucosidase for the first time, which could contribute to the development of functional additives for the prevention and treatment of type II diabetes.