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

Abstract

This work was designed to comparatively investigate 27 dietary flavonoids that act as α-glucosidase inhibitors and insulin sensitizers. On the basis of the results of an <i>in vitro</i> experiment of α-glucosidase inhibition, myricetin (IC₅₀ = 11.63 ± 0.36 μM) possessed the strongest inhibitory effect, followed by apigenin-7-<i>O</i>-glucoside (IC₅₀ = 22.80 ± 0.24 μM) and fisetin (IC₅₀ = 46.39 ± 0.34 μM). A three-dimensional quantitative structure-activity relationship model of α-glucosidase inhibitors with good predictive capability [comparative molecular field analysis, <i>q</i>² = 0.529, optimum number of components (ONC) = 10, <i>R</i>² = 0.996, <i>F</i> = 250.843, standard error of estimation (SEE) = 0.064, and two descriptors; comparative similarity index analysis, <i>q</i>² = 0.515, ONC = 10, <i>R</i>² = 0.997, <i>F</i> = 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 α-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-<i>O</i>-rutinoside, apigenin-7-<i>O</i>-glucoside, kaempferol-7-<i>O</i>-β-glucoside, and cyanidin-3-<i>O</i>-glucoside) that can act as insulin sensitizers and form strong combinations with four key protein targets involved in the insulin signaling pathway. Apigenin-7-<i>O</i>-glucoside (60 μM) 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-<i>O</i>-glucoside might serve as the most effective α-glucosidase inhibitor and insulin sensitizer. This work may guide diabetes patients to improve their condition through dietary therapy.