二氢异喹啉类BACE1抑制剂的特征结构及结合模式研究

引用本文: 吴倩, 李先国, 李燕, 杨凌. 二氢异喹啉类BACE1抑制剂的特征结构及结合模式研究[J]. 化学通报, 2016, 79(6): 509-515. shu

Citation: Wu Qian, Li Xianguo, Li Yan, Yang Ling. Study on the Structural Features and Binding Mode of Dihydroisoquinolines as BACE1 Inhibitors[J]. Chemistry, 2016, 79(6): 509-515. shu

二氢异喹啉类BACE1抑制剂的特征结构及结合模式研究

吴倩 ^1,2, ,
李先国 ^{1,
,} ,
李燕 ^3, ,
杨凌 ^4,

1.
1. 中国海洋大学海洋化学理论与工程技术教育部重点实验室青岛 266100;
2.
2. 潍坊学院化学化工与环境工程学院潍坊 261061;
3.
3. 大连理工大学化工与环境生命学部材料科学与化工系大连 116024;
4.
4. 中国科学院大连化学物理研究所药物资源开发研究组大连 116023

通讯作者: 李先国,男,教授,博士生导师,从事海洋化学研究,E-mail:lixg@ouc.edu.cn

基金项目:
潍坊学院青年科研基金项目（2014Z11）资助

摘要: β-分泌酶（BACE1）是水解淀粉样前体蛋白生成β-淀粉样多肽的关键限速酶，近年来已成为治疗阿尔茨海默症的一个理想靶点。本文以34个二氢异喹啉类BACE1抑制剂为研究对象，采用比较分子相似性指数（CoMSIA）法定量研究其结构与生物活性间的构效关系，并建立可靠的3D-QSAR预测模型，运用分子对接法分析其与受体BACE1间的结合模式。结果显示，基于立体场、疏水场和氢键供体场建立的CoMSIA模型稳定性良好、预测能力强（Q²=0.47，R_ncv²=0.93，R_pre²=0.95）。本研究所得模型和信息较好地解释了二氢异喹啉类BACE1抑制剂的结构特征及其与受体间的结合模式，为后续新型BACE1抑制剂的设计开发提供理论指导。

关键词:

English

Study on the Structural Features and Binding Mode of Dihydroisoquinolines as BACE1 Inhibitors

Wu Qian ^1,2, ,
Li Xianguo ^{1,
,} ,
Li Yan ^3, ,
Yang Ling ^4,

1.
1. Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, Ocean University of China, Qingdao 266100;
2.
2. Department of Chemical and Environmental Engineering, Weifang University, Weifang 261061;
3.
3. Department of Chemical Technology, Dalian University of Technology, Dalian 116024;
4.
4. Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023

Corresponding author: 李先国,男,教授,博士生导师,从事海洋化学研究,E-mail:lixg@ouc.edu.cn

Received Date: 18 October 2015
Fund Project:
潍坊学院青年科研基金项目（2014Z11）资助

Abstract: β-secretase (BACE1) is responsible for the initial cleavage of transmembrane amyloid precursor protein that leads to the production of β-amyloid (Aβ) peptides in the brain, and is a prime target for Alzheimer's disease (AD). In this paper, 34 kinds of dihydroisoquinoline derivatives as BACE1 inhibitors were studied by three-dimensional quantitative structure-activity relationship and molecular docking methods. The resultant optimal comparative molecular similarity indices analysis (CoMSIA) model, constructed based on the steric, hydrophobic and hydrogen-bond donor fields, displays a strong predictability (Q²=0.47, R_ncv²=0.93, R_pre²=0.95). This model and the derived information may help to provide better understanding of the structure features and binding mode of BACE1 inhibitors and to facilitate corresponding novel inhibitors' design.

Key words:

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二氢异喹啉类BACE1抑制剂的特征结构及结合模式研究

通讯作者: 李先国,男,教授,博士生导师,从事海洋化学研究,E-mail:lixg@ouc.edu.cn

English

Study on the Structural Features and Binding Mode of Dihydroisoquinolines as BACE1 Inhibitors

Corresponding author: 李先国,男,教授,博士生导师,从事海洋化学研究,E-mail:lixg@ouc.edu.cn

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中国化学会秘书处

二氢异喹啉类BACE1抑制剂的特征结构及结合模式研究

通讯作者: 李先国,男,教授,博士生导师,从事海洋化学研究,E-mail:lixg@ouc.edu.cn

English

Study on the Structural Features and Binding Mode of Dihydroisoquinolines as BACE1 Inhibitors

Corresponding author: 李先国,男,教授,博士生导师,从事海洋化学研究,E-mail:lixg@ouc.edu.cn

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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