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Pharmacophore-based drug design of AChE and BChE dual inhibitors as potential anti-Alzheimer's disease agents.
Bioorg Chem. 2021 09; 114:105149.BC

Abstract

For the Alzheimer's disease (AD) with complex pathogenesis, single target drugs represent one of the most effective therapeutic strategies in clinical. However, the traditional concept of "a disease, a target" is difficult to find very effective drugs, and multi-target drugs have already become new hot spot in drug development for this disease. In our present study, our efforts toward discovering new cholinesterase (ChE) inhibitors aided by computational methods will provide useful information as anti-AD agents in the future. The best 3D-QSAR acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors pharmacophore hypotheses Hypo1 A and Hypo1 B were generated and validated by HypoGen program in Discovery Studio 2016 based on the training set of flavonoids, and then they were used as 3D query for screening the ZINC database. Next, the hit molecules were then subjected to the ADMET and molecular docking study to prioritize the compounds. Finally, 6 compounds showed good estimated activities and promising ADMET properties. The result of best compound ZINC08751495 with AChE estimate activity (0.028), BChE estimate activity (1.55), AChE fit value (9.369), BChE fit value (8.415), AChE -CDOCKER ENERGY (30.22), BChE -CDOCKER ENERGY (33.13) has the potential for further development as a supplement to treat Alzheimer's disease.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Gao H
School of Life Science, Ludong University, Yantai, Shandong 264025, China. Electronic address: gaohongw369@ldu.edu.cn.
Jiang Y
Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China.
Zhan J
School of Life Science, Ludong University, Yantai, Shandong 264025, China.
Sun Y
School of Life Science, Ludong University, Yantai, Shandong 264025, China.

MeSH

AcetylcholinesteraseAlzheimer DiseaseButyrylcholinesteraseCholinesterase InhibitorsDose-Response Relationship, DrugDrug DesignHumansMolecular Docking SimulationMolecular StructureNeuroprotective AgentsStructure-Activity Relationship

Pub Type(s)

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

Language

eng

PubMed ID

34252860

Citation

Gao, Hongwei, et al. "Pharmacophore-based Drug Design of AChE and BChE Dual Inhibitors as Potential anti-Alzheimer's Disease Agents." Bioorganic Chemistry, vol. 114, 2021, p. 105149.
Gao H, Jiang Y, Zhan J, et al. Pharmacophore-based drug design of AChE and BChE dual inhibitors as potential anti-Alzheimer's disease agents. Bioorg Chem. 2021;114:105149.
Gao, H., Jiang, Y., Zhan, J., & Sun, Y. (2021). Pharmacophore-based drug design of AChE and BChE dual inhibitors as potential anti-Alzheimer's disease agents. Bioorganic Chemistry, 114, 105149. https://doi.org/10.1016/j.bioorg.2021.105149
Gao H, et al. Pharmacophore-based Drug Design of AChE and BChE Dual Inhibitors as Potential anti-Alzheimer's Disease Agents. Bioorg Chem. 2021;114:105149. PubMed PMID: 34252860.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacophore-based drug design of AChE and BChE dual inhibitors as potential anti-Alzheimer's disease agents. AU - Gao,Hongwei, AU - Jiang,Yingying, AU - Zhan,Jiuyu, AU - Sun,Yingni, Y1 - 2021/07/07/ PY - 2021/03/11/received PY - 2021/05/25/revised PY - 2021/07/02/accepted PY - 2021/7/13/pubmed PY - 2021/12/15/medline PY - 2021/7/12/entrez KW - Acetylcholinesterase KW - Alzheimer's disease KW - Butyrylcholinesterase KW - Molecular docking KW - Pharmacophore models KW - Virtual screening SP - 105149 EP - 105149 JF - Bioorganic chemistry JO - Bioorg Chem VL - 114 N2 - For the Alzheimer's disease (AD) with complex pathogenesis, single target drugs represent one of the most effective therapeutic strategies in clinical. However, the traditional concept of "a disease, a target" is difficult to find very effective drugs, and multi-target drugs have already become new hot spot in drug development for this disease. In our present study, our efforts toward discovering new cholinesterase (ChE) inhibitors aided by computational methods will provide useful information as anti-AD agents in the future. The best 3D-QSAR acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors pharmacophore hypotheses Hypo1 A and Hypo1 B were generated and validated by HypoGen program in Discovery Studio 2016 based on the training set of flavonoids, and then they were used as 3D query for screening the ZINC database. Next, the hit molecules were then subjected to the ADMET and molecular docking study to prioritize the compounds. Finally, 6 compounds showed good estimated activities and promising ADMET properties. The result of best compound ZINC08751495 with AChE estimate activity (0.028), BChE estimate activity (1.55), AChE fit value (9.369), BChE fit value (8.415), AChE -CDOCKER ENERGY (30.22), BChE -CDOCKER ENERGY (33.13) has the potential for further development as a supplement to treat Alzheimer's disease. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/34252860/Pharmacophore_based_drug_design_of_AChE_and_BChE_dual_inhibitors_as_potential_anti_Alzheimer's_disease_agents_ DB - PRIME DP - Unbound Medicine ER -