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The discovery of new acetylcholinesterase inhibitors derived from pharmacophore modeling, virtual screening, docking simulation and bioassays.
Mol Biosyst. 2016 11 15; 12(12):3734-3742.MB

Abstract

Hyperactivity of acetylcholinesterase (AChE) in the brain is the immediate cause of Alzheimer's disease (AD), which is one of the most prevalent fatal diseases afflicting numerous older people. In this research, an in silico study was carried out to find potential AChE inhibitors from a large chemical library. With clustering and lots of comprehensive analysis, some molecules were screened using in vitro bioassays. The IC50 values against AChE ranged from 33.620 to 101.570 μM, while the inhibition ratios at 50 μM ranged from 11.37% to 77.35%. The binding mode between the inhibitor and the binding sites of AChE was studied. Four residues (Tyr133, Tyr124, Ser203 and Trp86) were suggested to be crucial because they can form hydrogen bonds with the ligand. Therefore, ZYQ1 and its derivatives might represent a promising starting point for the development of highly potent lead compounds for the treatment of AD.

Authors+Show Affiliations

Zhang Y
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. zuozhili@mail.kib.ac.cn and University of the Chinese Academy of Sciences, Beijing 100049, China.
Zhang S
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. zuozhili@mail.kib.ac.cn.
Xu G
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. zuozhili@mail.kib.ac.cn and University of the Chinese Academy of Sciences, Beijing 100049, China.
Yan H
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. zuozhili@mail.kib.ac.cn.
Pu Y
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. zuozhili@mail.kib.ac.cn.
Zuo Z
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. zuozhili@mail.kib.ac.cn and Yunnan Key Laboratory of Natural Medicinal Chemistry, Yunnan, 650201, China.

MeSH

AcetylcholinesteraseBinding SitesBiological AssayCholinesterase InhibitorsCluster AnalysisComputer SimulationDrug DiscoveryHydrophobic and Hydrophilic InteractionsInhibitory Concentration 50LigandsMolecular ConformationMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureProtein BindingWorkflow

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27801451

Citation

Zhang, Yunqin, et al. "The Discovery of New Acetylcholinesterase Inhibitors Derived From Pharmacophore Modeling, Virtual Screening, Docking Simulation and Bioassays." Molecular BioSystems, vol. 12, no. 12, 2016, pp. 3734-3742.
Zhang Y, Zhang S, Xu G, et al. The discovery of new acetylcholinesterase inhibitors derived from pharmacophore modeling, virtual screening, docking simulation and bioassays. Mol Biosyst. 2016;12(12):3734-3742.
Zhang, Y., Zhang, S., Xu, G., Yan, H., Pu, Y., & Zuo, Z. (2016). The discovery of new acetylcholinesterase inhibitors derived from pharmacophore modeling, virtual screening, docking simulation and bioassays. Molecular BioSystems, 12(12), 3734-3742.
Zhang Y, et al. The Discovery of New Acetylcholinesterase Inhibitors Derived From Pharmacophore Modeling, Virtual Screening, Docking Simulation and Bioassays. Mol Biosyst. 2016 11 15;12(12):3734-3742. PubMed PMID: 27801451.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The discovery of new acetylcholinesterase inhibitors derived from pharmacophore modeling, virtual screening, docking simulation and bioassays. AU - Zhang,Yunqin, AU - Zhang,Shuqun, AU - Xu,Guowei, AU - Yan,Hui, AU - Pu,Yinglan, AU - Zuo,Zhili, PY - 2016/11/2/pubmed PY - 2017/7/25/medline PY - 2016/11/2/entrez SP - 3734 EP - 3742 JF - Molecular bioSystems JO - Mol Biosyst VL - 12 IS - 12 N2 - Hyperactivity of acetylcholinesterase (AChE) in the brain is the immediate cause of Alzheimer's disease (AD), which is one of the most prevalent fatal diseases afflicting numerous older people. In this research, an in silico study was carried out to find potential AChE inhibitors from a large chemical library. With clustering and lots of comprehensive analysis, some molecules were screened using in vitro bioassays. The IC50 values against AChE ranged from 33.620 to 101.570 μM, while the inhibition ratios at 50 μM ranged from 11.37% to 77.35%. The binding mode between the inhibitor and the binding sites of AChE was studied. Four residues (Tyr133, Tyr124, Ser203 and Trp86) were suggested to be crucial because they can form hydrogen bonds with the ligand. Therefore, ZYQ1 and its derivatives might represent a promising starting point for the development of highly potent lead compounds for the treatment of AD. SN - 1742-2051 UR - https://www.unboundmedicine.com/medline/citation/27801451/The_discovery_of_new_acetylcholinesterase_inhibitors_derived_from_pharmacophore_modeling_virtual_screening_docking_simulation_and_bioassays_ DB - PRIME DP - Unbound Medicine ER -
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