Effects of Different Dietary Flavonoids on Dipeptidyl Peptidase-IV Activity and Expression: Insights into Structure–Activity Relationship

Abstract

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 <i>in vitro</i> experiment show that isorhamnetin-3-<i>O</i>-glucoside (IC₅₀, 6.53 ± 0.280 μM) had the strongest inhibition followed by cyanidin-3-<i>O</i>-glucoside (IC₅₀, 8.26 ± 0.143 μM) and isorhamnetin-3-<i>O</i>-rutinoside (IC₅₀, 8.57 ± 0.422 μM). A 3D QSAR model [comparative molecular field analysis, <i>q</i>² = 0.502, optimum number of components (ONC) = 3, <i>R</i>² = 0.983, <i>F</i> = 404.378, standard error of estimation (SEE) = 0.070, and two descriptors; comparative similarity index analysis, <i>q</i>² = 0.580, ONC = 10, <i>R</i>² = 0.999, <i>F</i> = 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.