Inhibition and structural reliability of prenylated flavones from the stem bark of Morus lhou on β-secretase (BACE-1)
Inhibition and structural reliability of prenylated flavones from the stem bark of Morus lhou on β-secretase (BACE-1)
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DOI：
10.1016/j.bmcl.2011.03.060
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发表时间：
2011-05-15
影响因子：
2.7
通讯作者：
Park, Ki Hun
中科院分区：
文献类型：
--
作者：
Cho, Jung Keun;Ryu, Young Bae;Park, Ki Hun
β-分泌酶的作用与阿尔茨海默病的发病密切相关。因此，β-分泌酶抑制剂的开发对于防治这种疾病至关重要，这种疾病威胁着越来越多的人口，并且随着人口老龄化而变得越来越重要。在此，我们表明，从桑黄酮有效地抑制β-分泌酶。我们在这篇手稿的目的是探索天然化合物的抑制动力学，并开发一个phamacophore模型，详细说明了负责抑制活性的关键特征。化合物对β-分泌酶抑制的IC 50值测定为3.4 - 146.1 μ M。异戊烯化黄酮2（IC 50 = 3.4 μ M）比其母体化合物noratocarpetin 1（IC 50 = 60.6 μ M）有效20倍。较强的活性与B环上的间苯二酚部分和C-3处的异戊二烯基官能团有关。动力学分析表明，四个有效化合物（1 - 4）具有非竞争性作用模式。黄酮类化合物对β-分泌酶的结合亲和力与其IC50值和非竞争性抑制模式相关。(C)2011爱思唯尔有限公司版权所有。
The action of beta-secretase is strongly tied to the onset of Alzheimer's disease. The development of inhibitors of beta-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 beta-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 IC50 values of compounds for beta-secretase inhibition were determined to range between 3.4 and 146.1 mu M. Prenylated flavone 2 (IC50 = 3.4 mu M) was 20 times more effective than its parent compound, noratocarpetin 1 (IC50 = 60.6 mu M). 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 beta-secretase calculated using in silico docking experiments correlated well with their IC50 values and noncompetitive inhibition modes. (C) 2011 Elsevier Ltd. All rights reserved.