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Molecules 2017, 22(8), 1254; doi:10.3390/molecules22081254

Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer’s Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches

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1,4,5,* , 1,* and 1,4,5,*
1
Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China
2
Beijing Institute for Drug Control, Beijing 102206, China
3
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China
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Beijing Key Laboratory of Drug Target Research and Drug Screening, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
5
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
*
Authors to whom correspondence should be addressed.
Received: 13 July 2017 / Revised: 24 July 2017 / Accepted: 25 July 2017 / Published: 26 July 2017
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [9628 KB, uploaded 30 July 2017]   |  

Abstract

DL0410, containing biphenyl and piperidine skeletons, was identified as an acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor through high-throughput screening assays, and further studies affirmed its efficacy and safety for Alzheimer’s disease treatment. In our study, a series of novel DL0410 derivatives were evaluated for inhibitory activities towards AChE and BuChE. Among these derivatives, compounds 6-1 and 7-6 showed stronger AChE and BuChE inhibitory activities than DL0410. Then, pharmacophore modeling and three-dimensional quantitative structure activity relationship (3D-QSAR) models were performed. The R2 of AChE and BuChE 3D-QSAR models for training set were found to be 0.925 and 0.883, while that of the test set were 0.850 and 0.881, respectively. Next, molecular docking methods were utilized to explore the putative binding modes. Compounds 6-1 and 7-6 could interact with the amino acid residues in the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE/BuChE, which was similar with DL0410. Kinetics studies also suggested that the three compounds were all mixed-types of inhibitors. In addition, compound 6-1 showed better absorption and blood brain barrier permeability. These studies provide better insight into the inhibitory behaviors of DL0410 derivatives, which is beneficial for rational design of AChE and BuChE inhibitors in the future. View Full-Text
Keywords: cholinesterase inhibitor; Alzheimer’s disease; DL0410; 3D-QSAR; molecular docking; kinetics cholinesterase inhibitor; Alzheimer’s disease; DL0410; 3D-QSAR; molecular docking; kinetics
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MDPI and ACS Style

Pang, X.; Fu, H.; Yang, S.; Wang, L.; Liu, A.-L.; Wu, S.; Du, G.-H. Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer’s Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches. Molecules 2017, 22, 1254.

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