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Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease.
J Mol Model. 2015 Oct; 21(10):277.JM

Abstract

Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).

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Publisher Full Text (DOI)

Authors+Show Affiliations

Zhou A
Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, China. Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Chinese Medicine, 103 Meishan Road, Hefei, 230038, Anhui, China.
Hu J
Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA. Key Laboratory of Medicinal and Edible Plants Resources Development, School of Bioengineering, Chengdu University, Chengdu, 610106, China.
Wang L
Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA. Key Laboratory of Medicinal and Edible Plants Resources Development, School of Bioengineering, Chengdu University, Chengdu, 610106, China.
Zhong G
Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Chinese Medicine, 103 Meishan Road, Hefei, 230038, Anhui, China.
Pan J
Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, China. panjian78@sina.cn.
Wu Z
Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, China.
Hui A
Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, China. haling@mail.ustc.edu.cn.

MeSH

AcetylcholinesteraseAlzheimer DiseaseCholinesterase InhibitorsHydrogen BondingMolecular ConformationMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureQuantitative Structure-Activity RelationshipTacrine

Pub Type(s)

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

Language

eng

PubMed ID

26438408

Citation

Zhou, An, et al. "Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study of Tacrine Derivatives as Potential Acetylcholinesterase (AChE) Inhibitors of Alzheimer's Disease." Journal of Molecular Modeling, vol. 21, no. 10, 2015, p. 277.
Zhou A, Hu J, Wang L, et al. Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease. J Mol Model. 2015;21(10):277.
Zhou, A., Hu, J., Wang, L., Zhong, G., Pan, J., Wu, Z., & Hui, A. (2015). Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease. Journal of Molecular Modeling, 21(10), 277. https://doi.org/10.1007/s00894-015-2797-8
Zhou A, et al. Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study of Tacrine Derivatives as Potential Acetylcholinesterase (AChE) Inhibitors of Alzheimer's Disease. J Mol Model. 2015;21(10):277. PubMed PMID: 26438408.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease. AU - Zhou,An, AU - Hu,Jianping, AU - Wang,Lirong, AU - Zhong,Guochen, AU - Pan,Jian, AU - Wu,Zeyu, AU - Hui,Ailing, Y1 - 2015/10/05/ PY - 2015/03/28/received PY - 2015/08/24/accepted PY - 2015/10/7/entrez PY - 2015/10/7/pubmed PY - 2016/7/12/medline KW - 3D-QSAR KW - AChE inhibitor KW - Alzheimer’s disease KW - Molecular dynamics KW - Tacrine SP - 277 EP - 277 JF - Journal of molecular modeling JO - J Mol Model VL - 21 IS - 10 N2 - Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green). SN - 0948-5023 UR - https://www.unboundmedicine.com/medline/citation/26438408/Combined_3D_QSAR_molecular_docking_and_molecular_dynamics_study_of_tacrine_derivatives_as_potential_acetylcholinesterase__AChE__inhibitors_of_Alzheimer's_disease_ DB - PRIME DP - Unbound Medicine ER -