title: Inhibition and structural reliability of prenylated flavones from the stem bark of Morus lhou on β-secretase (BACE-1).
abstract: The action of β-secretase is strongly tied to the onset of Alzheimer's disease. The development of inhibitors of β-secretase is thus critical to combating this disease, which threatens an ever increasing number of the population and grows in importance as the population ages. Herein we show that flavones from Morus lhou potently inhibit β-secretase. Our aim in this manuscript is to explore the inhibitory kinetics of natural compounds and develop a phamacophore model which details the critical features responsible for inhibitory activity. The IC(50) values of compounds for β-secretase inhibition were determined to range between 3.4 and 146.1 μM. Prenylated flavone 2 (IC(50)=3.4 μM) was 20 times more effective than its parent compound, noratocarpetin 1 (IC(50)=60.6 μM). The stronger activity was related with resorcinol moiety on B-ring and isoprenyl functionality at C-3. Kinetic analysis shows that the four effective compounds (1-4) have a noncompetitive mode of action. The binding affinity of flavones for β-secretase calculated using in silico docking experiments correlated well with their IC(50) values and noncompetitive inhibition modes.
authors.affiliation: Division of Applied Life Science (BK21 Program, IALS), Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Jung Keun
authors.initials: JK
authors.lastname: Cho
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Ryu
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Curtis-Long
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Doman
authors.initials: D
authors.lastname: Kim
authors.forename: Sun
authors.initials: S
authors.lastname: Lee
authors.forename: Woo Song
authors.initials: WS
authors.lastname: Lee
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D047309:Flavones / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D031625:Morus / Q000737:chemistry*; D024301:Plant Bark / Q000737:chemistry*; D018547:Plant Stems / Q000737:chemistry*; D054876:Prenylation; D013722:Teprotide / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047309:Flavones; D013722:Teprotide; D053829:Amyloid Precursor Protein Secretases