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 Jul 26; 22(8)M

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.

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Authors+Show Affiliations

Pang X

Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. pangxiaocong@imm.ac.cn.

Fu H

Beijing Institute for Drug Control, Beijing 102206, China. wlin@imm.ac.cn.

Yang S

Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China. fuhuifree@sina.com.

Wang L

Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. yangsl@imm.ac.cn.

Liu AL

Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. liuailin@imm.ac.cn. Beijing Key Laboratory of Drug Target Research and Drug Screening, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. liuailin@imm.ac.cn. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. liuailin@imm.ac.cn.

Wu S

Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. ws@imm.ac.cn.

Du GH

Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China. dugh@imm.ac.cn. Beijing Key Laboratory of Drug Target Research and Drug Screening, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. dugh@imm.ac.cn. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. dugh@imm.ac.cn.

MeSH

AcetylcholinesteraseAlzheimer DiseaseAnti-Anxiety AgentsBinding SitesButyrylcholinesteraseCholinesterase InhibitorsHigh-Throughput Screening AssaysHumansKineticsModels, MolecularMolecular Docking SimulationMolecular StructureProtein BindingQuantitative Structure-Activity Relationship

Pub Type(s)

Evaluation Study

Journal Article

Language

eng

PubMed ID

28933746

Citation

Pang, Xiaocong, et al. "Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer's Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches." Molecules (Basel, Switzerland), vol. 22, no. 8, 2017.

Pang X, Fu H, Yang S, et al. 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(8).

Pang, X., Fu, H., Yang, S., Wang, L., Liu, A. L., Wu, S., & Du, G. H. (2017). Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer's Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches. Molecules (Basel, Switzerland), 22(8). https://doi.org/10.3390/molecules22081254

Pang X, et al. 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 Jul 26;22(8) PubMed PMID: 28933746.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer's Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches. AU - Pang,Xiaocong, AU - Fu,Hui, AU - Yang,Shilun, AU - Wang,Lin, AU - Liu,Ai-Lin, AU - Wu,Song, AU - Du,Guan-Hua, Y1 - 2017/07/26/ PY - 2017/07/13/received PY - 2017/07/24/revised PY - 2017/07/25/accepted PY - 2017/9/22/entrez PY - 2017/9/22/pubmed PY - 2018/10/5/medline KW - 3D-QSAR KW - Alzheimer’s disease KW - DL0410 KW - cholinesterase inhibitor KW - kinetics KW - molecular docking JF - Molecules (Basel, Switzerland) JO - Molecules VL - 22 IS - 8 N2 - 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. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/28933746/Evaluation_of_Novel_Dual_Acetyl__and_Butyrylcholinesterase_Inhibitors_as_Potential_Anti_Alzheimer's_Disease_Agents_Using_Pharmacophore_3D_QSAR_and_Molecular_Docking_Approaches_ DB - PRIME DP - Unbound Medicine ER -

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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 Jul 26; 22(8)M