MTDLs Design on AChE （Acetylcholinesterase） and β-Secretase （BACE-1）： 3D-QSAR and Molecular Docking Studies

作     者：Jiancheng Shi Wentong Tu Jiarong Sheng Chusheng Huang 

作者机构：College of Chemistry and Material Sciences Guangxi Teachers Education University Nanning 530001 China 

基　　金：Acknowledgments The authors acknowledge the financial support of the Natural Science Foundation of Guangxi Province (No. 2013GXNSFAA019019) and the Natural Science Foundation of Guangxi Province (No. 2013GXNSFAA019041) 

出 版 物：《Journal of Pharmacy and Pharmacology》 (药剂与药理学（英文版）)

年 卷 期：2015年第3卷第10期

页      码：489-501页

摘      要：To find promising new multitargeted AD （Alzheimer＇s disease） inhibitors, the 3D-QSAR （three-dimensional quantitative structure-activity relationship） model for 32 AD inhibitors was established by using the CoMFA （comparative molecular field analysis） and CoMSIA （comparative molecular similarity index analysis） methods. Results showed that the CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient （q2） and a non-cross-validated coefficient （R2）, and the binding modes obtained by molecular docking were in agreement with the 3D-QSAR results, which suggests that the present 3D-QSAR model has good predictive capability to guide the design and structural modification of novel multitargeted AD inhibitors. Meanwhile, we found that one side of inhibitory molecule should be small group so that it would be conductive to enter the gorge to interact with the catalytic active sites of AChE （acetylcholinesterase）, and the other side of inhibitory molecule should be large group so that it would be favorable for interaction with the peripheral anionic site of ACHE. Furthermore, based on the 3D-QSAR model and the binding modes of AChE and [3-secretase （BACE-1）, the designed molecules could both act on dual binding sites of AChE （catalytic and peripheral sites） and dual targets （ACHE and BACE-1）. We hope that our results could provide hints for the design of new multitargeted AD derivatives with more potency and selective activity.

主 题 词：3D-QSAR molecular docking ACHE BACE-1 MTDLs. 

学科分类：1007[医学-药学类] 10[医学] 

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