Citrus Flavonoids Luteolin, Apigenin, and Quercetin Inhibit Glycogen Synthase Kinase-3β Enzymatic Activity by Lowering the Interaction Energy Within the Binding Cavity

Pancreatic cancer studies have shown that inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) leads to decreased cancer cell proliferation and survival by abrogating nuclear factor kappa B (NF kappa B) activity. In this investigation, various citrus compounds, including flavonoids, phenolic acids, and limonoids, were individually investigated for their inhibitory effects on GSK-3 beta by using a luminescence assay. Of the 22 citrus compounds tested, the flavonoids luteolin, apigenin, and quercetin had the highest inhibitory effects on GSK-3 beta, with 50% inhibitory values of 1.5, 1.9, and 2.0 mu M, respectively. Molecular dockings were then performed to determine the potential interactions of each citrus flavonoid with GSK-3 beta. Luteolin, apigenin, and quercetin were predicted to fit within the binding pocket of GSK-3 beta with low interaction energies (-76.4, -76.1, and -84.6 kcal.mol(-1), respectively) and low complex energies (-718.1, -688.1, and -719.7 kcal.mol(-1), respectively). Our results indicate that several citrus flavonoids inhibit GSK-3 beta activity and suggest that these have potential to suppress the growth of pancreatic tumors.