Comprehensive 3D-QSAR and binding mode of BACE-1 inhibitors using R-group search and molecular docking
Comprehensive 3D-QSAR and binding mode of BACE-1 inhibitors using R-group search and molecular docking
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DOI：
10.1016/j.jmgm.2013.08.003
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发表时间：
2013-09-01
影响因子：
2.9
通讯作者：
Liang, Guizhao
中科院分区：
文献类型：
--
作者：
Huang, Dandan;Liu, Yonglan;Liang, Guizhao
β-酶（BACE）在淀粉样蛋白前体蛋白的加工中发挥积极作用，从而导致大脑中淀粉样蛋白β（A β）的产生，是对抗阿尔茨海默病的主要治疗靶点。本研究旨在研究BACE-1抑制剂的三维定量构效关系及其结合模式。我们建立了一个3D-QSAR模型，涉及99个训练BACE-1抑制剂的基础上Topomer CoMFA，并采用26个分子来验证所获得的模型的外部预测能力。拟合建模、留一交叉验证和外部验证的复相关系数分别为0.966、0.767和0.784。拓扑异构体搜索被用作ZINC数据库（2012）中铅样化合物的虚拟筛选工具;因此，我们成功设计了30种新分子，其活性高于所有训练和测试抑制剂。此外，利用Surflex-dock技术研究了抑制剂与BACE-1酶的结合方式。结果表明，这些抑制剂与BACE-1的ASP 93、THR 133、GLN 134、ASP 289、GLY 291、THR 292、THR 293、ASN 294、ARG 296和SER 386相关的关键位点密切结合。(C)2013 Elsevier Inc. All rights reserved.
The beta-enzyme (BACE), which takes an active part in the processing of amyloid precursor protein, thereby leads to the production of amyloid-beta (A beta) in the brain, is a major therapeutic target against Alzheimer's disease. The present study is aimed at studying 3D-QSAR of BACE-1 inhibitors and their binding mode. We build a 3D-QSAR model involving 99 training BACE-1 inhibitors based on Topomer CoMFA, and 26 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting modeling, leave one out cross validation, and external validation are 0.966, 0.767 and 0.784, respectively. Topomer search is used as a tool for virtual screening in lead-like compounds of ZINC databases (2012); as a result, we successfully design 30 new molecules with higher activity than that of all training and test inhibitors. Besides, Surflex-dock is employed to explore binding mode of the inhibitors studied when acting with BACE-1 enzyme. The result shows that the inhibitors closely interact with the key sites related to ASP93, THR133, GLN134, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and SER386 of BACE-1. (C) 2013 Elsevier Inc. All rights reserved.