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 in vitro experiment of α-glucosidase inhibition, myricetin (IC50 = 11.63 ± 0.36 μM) possessed the strongest inhibitory effect, followed by apigenin-7-O-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, 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 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-O-rutinoside, apigenin-7-O-glucoside, kaempferol-7-O-β-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 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-O-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.

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The present study investigated the phenolic profiles and antioxidant properties of different fractions from Prinsepia utilis Royle fruits using molecular docking analysis to delineate their inhibition toward digestive enzymes. A total of 20 phenolics was identified and quantified. Rutin, quercetin-3-O-glucoside, and isorhamnetin-3-O-rutinoside were the major phenolic compounds in the total phenolic fraction and flavonoid-rich fraction. The anthocyanin-rich fraction mainly contained cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside. All of the fractions exhibited strong radical scavenging activities and good inhibition on cellular reactive oxygen species (ROS) generation in H2O2-induced HepG2 cells, as evaluated by DPPH and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assays. Moreover, the powerful inhibitory effects of those fractions against pancreatic lipase and α-glucosidase were observed. The major phenolic compounds that were found in the three fractions also showed good digestive enzyme inhibitory activities in a dose-dependent manner. Molecular docking analysis revealed the underlying inhibition mechanisms of those phenolic standards against digestive enzymes, and the theoretical analysis data were consistent with the experimental results.

The inhibitory effects of 30 dietary flavonoids on dipeptidyl peptidase-IV (DPP-IV) were investigated to illustrate their quantitative structure−activity relationship (QSAR) and further explore their inhibition at the cellular level. Results of in vitro experiment show that isorhamnetin-3-O-glucoside (IC 50 , 6.53 ± 0.280 μM) had the strongest inhibition followed by cyanidin-3-Oglucoside (IC 50 , 8.26 ± 0.143 μM) and isorhamnetin-3-O-rutinoside (IC 50 , 8.57 ± 0.422 μM). A 3D QSAR model [comparative molecular field analysis, q 2 = 0.502, optimum number of components (ONC) = 3, R 2 = 0.983, F = 404.378, standard error of estimation (SEE) = 0.070, and two descriptors; comparative similarity index analysis, q 2 = 0.580, ONC = 10, R 2 = 0.999, F = 1617.594, SEE = 0.022, and four descriptors] indicates that the DPP-IV inhibition of flavonoid was facilitated by crucial structural factors. Position 3 of ring C favored bulky, hydrogen bond acceptors and hydrophilic and electron-donating substituents. The presence of minor and electron-withdrawing groups at position 4′ of ring B and positions 5 and 7 of ring A could improve DPP-IV inhibition. Moreover, the three flavonoids mentioned above could effectively suppress DPP-IV activity and expression in Caco-2 cells. This work may supply new insights into dietary flavonoids as DPP-IV inhibitors for controlling blood glucose.