Bioorganic & Medicinal Chemistry Letters 2011-05-15

Inhibition and structural reliability of prenylated flavones from the stem bark of Morus lhou on β-secretase (BACE-1).

Jung Keun Cho, Young Bae Ryu, Marcus J Curtis-Long, Ji Young Kim, Doman Kim, Sun Lee, Woo Song Lee, Ki Hun Park

Index: Bioorg. Med. Chem. Lett. 21(10) , 2945-8, (2011)

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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.Copyright © 2011 Elsevier Ltd. All rights reserved.