title: Citrus flavonoids luteolin, apigenin, and quercetin inhibit glycogen synthase kinase-3β enzymatic activity by lowering the interaction energy within the binding cavity.
abstract: Pancreatic cancer studies have shown that inhibition of glycogen synthase kinase-3β (GSK-3β) leads to decreased cancer cell proliferation and survival by abrogating nuclear factor κB (NFκB) activity. In this investigation, various citrus compounds, including flavonoids, phenolic acids, and limonoids, were individually investigated for their inhibitory effects on GSK-3β by using a luminescence assay. Of the 22 citrus compounds tested, the flavonoids luteolin, apigenin, and quercetin had the highest inhibitory effects on GSK-3β, with 50% inhibitory values of 1.5, 1.9, and 2.0 μM, respectively. Molecular dockings were then performed to determine the potential interactions of each citrus flavonoid with GSK-3β. Luteolin, apigenin, and quercetin were predicted to fit within the binding pocket of GSK-3β 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-3β activity and suggest that these have potential to suppress the growth of pancreatic tumors.
authors: Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors: Jodee L
authors: JL
authors: Johnson
authors: Sanjeewa G
authors: SG
authors: Rupasinghe
authors: Felicia
authors: F
authors: Stefani
authors: Mary A
authors: MA
authors: Schuler
authors: Elvira
authors: E
authors: Gonzalez de Mejia
mesh_terms: D000595:Amino Acid Sequence; D047310:Apigenin / Q000494:pharmacology*; D001665:Binding Sites; D002957:Citrus / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000628:therapy; D017434:Protein Structure, Tertiary; D011794:Quercetin / Q000494:pharmacology*; D016415:Sequence Alignment
chemical_list: D004791:Enzyme Inhibitors; D047310:Apigenin; D011794:Quercetin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D047311:Luteolin