Investigation of C-glycosylated apigenin and luteolin derivatives’ effects on protein tyrosine phosphatase 1B inhibition with molecular and cellular approaches

Abstract

In our previous study, we investigated C-glycosylated apigenin and luteolin derivatives’ antidiabetic potential via protein tyrosine phosphatase 1B (PTP1B) inhibition in vitro, and found that they exhibited varying degrees of effect on PTP1B (IC50 = 17.76, 24.76, 7.62, 24.54, 6.70, and 57.11 µM for isovitexin, apigenin, vitexin, isoorientin, luteolin, and orientin, respectively). However, the precise molecular mechanisms in apigenin and luteolin derivatives’ PTP1B inhibition remain unclear. Therefore, in this study, we examined C-glycosylated apigenin and luteolin derivatives’ PTP1B inhibition via molecular docking simulation and PTP1B expression at the cellular level in insulin-resistant C2C12 cells. Kinetic studies revealed that apigenin, luteolin, and isoorientin were competitive, vitexin and isovitexin mixed-type, and orientin noncompetitive inhibitors of PTP1B. Docking simulations of these flavonoids demonstrated different negative binding energies and close proximity to residues in PTP1B’s binding pocket. The number of hydrogen bonds and other interactions determined the strength of the protein-inhibitor interaction. Further, we also found that apigenin and luteolin derivatives stimulate glucose uptake in insulin-resistant C2C12 cells. Therefore, we speculate that the C-glycosylation apigenin and luteolin derivatives at the C-6 and C-8 positions affect PTP1B inhibition greatly depending upon the type of mode of inhibition and binding affinity with the PTP1B expression level. Thus, the study contributes to our knowledge of the mechanisms by which C-glycosylated flavonoids exert varying degrees of PTP1B inhibition activity.