Comparative Study of Dietary Flavonoids with Different Structures as α-Glucosidase Inhibitors and Insulin Sensitizers

This work was designed to comparatively investigate 27 dietary flavonoids that act as alpha-glucosidase inhibitors and insulin sensitizers. On the basis of the results of an in vitro experiment of alpha-glucosidase inhibition, myricetin (IC50 = 11.63 +/- 0.36 mu M) possessed the strongest inhibitory effect, followed by apigenin-7-0-glucoside (IC50 = 22.80 +/- 0.24 mu M) and fisetin (IC50 = 46.39 +/- 0.34 mu M). A three-dimensional quantitative structure activity relationship model of a-glucosidase inhibitors with good predictive capability [comparative molecular field analysis, q(2) = 0.529, optimum number of components (ONC) = 10, R-2 = 0.996, F = 250.843, standard error of estimation (SEE) = 0.064, and two descriptors; comparative similarity index analysis, q(2) = 0.515, ONC = 10, R-2 = 0.997, F = 348.301, SEE = 0.054, and four descriptors] was established and indicated that meta positions of ring B favored bulky and minor, electron-withdrawing, and hydrogen bond donor groups. The presence of electron-donating and hydrogen bond acceptor groups at position 4' of ring B could improve alpha-glucosidase activity. Position 3 of ring C favored minor, electron-donating, and hydrogen bond donor groups, whereas position 7 of ring A favored bulky and hydrogen bond acceptor groups. Molecular docking screened five flavonoids (baicalein, isorhamnetin-3-O-rutinoside, apigenin7-O-glucoside, kaempferol-7-O-beta-glucoside, and cyanidin-3-O-glucoside) that can act as insulin sensitizers and form strong combinations with four key protein targets involved in the insulin signaling pathway. Apigenin-7-O-glucoside (60 mu M) can effectively improve insulin resistance, and glucose uptake increased by approximately 73.06% relative to the model group of insulin-resistant HepG2 cells. Therefore, apigenin-7-O-glucoside might serve as the most effective alpha-glucosidase inhibitor and insulin sensitizer. This work may guide diabetes patients to improve their condition through dietary therapy.