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In silico identification of AChE and PARP-1 dual-targeted inhibitors of Alzheimer's disease.
J Mol Model. 2018 Jun 05; 24(7):151.JM

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disease of the elderly that seriously affects the quality of life and the life expectancy of those affected. There is, as yet, no effective drug treatment of AD, although several acetylcholinesterase (AChE) inhibitors and a glutamate antagonist can provide relief from its symptoms. Recent studies have indicated that the overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) may promote nerve cell death in the brains of AD patients, implying that PARP-1 inhibition may have therapeutic value for the treatment of AD. Therefore, it is important to investigate novel agents with both AChE- and PARP-1-inhibitory bioactivities. In this study, the structure-based virtual screening of PARP-1 inhibitors was performed to search for potential agents with high affinities for AChE. The dynamic stability of the selected AChE-ligand complexes was investigated by molecular dynamics (MD) simulation. Two compounds, CID57390505 and CID71605390, showed high affinities for and stability in complex with AChE in docking and MD simulations. Thus, our in silico research identified two compounds with AChE and PARP-1 dual-targeted activities, indicating that this technique could aid attempts to develop more potent agents against AD.

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Authors+Show Affiliations

Hu XM
College of Pharmacy, Shanghai University of Medicine & Health Sciences, Shanghai, China. Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
Dong W
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
Cui ZW
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
Gao CZ
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
Yu ZJ
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
Yuan Q
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China. Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, Hubei Province, China. New Drugs Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
Min ZL
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China. minzhenli@wust.edu.cn. Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, Hubei Province, China. minzhenli@wust.edu.cn. New Drugs Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China. minzhenli@wust.edu.cn.

MeSH

AcetylcholinesteraseAlzheimer DiseaseCholinesterase InhibitorsDrug DiscoveryEnzyme InhibitorsHumansInhibitory Concentration 50LigandsMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructurePoly (ADP-Ribose) Polymerase-1Quantitative Structure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29869722

Citation

Hu, Xia-Min, et al. "In Silico Identification of AChE and PARP-1 Dual-targeted Inhibitors of Alzheimer's Disease." Journal of Molecular Modeling, vol. 24, no. 7, 2018, p. 151.
Hu XM, Dong W, Cui ZW, et al. In silico identification of AChE and PARP-1 dual-targeted inhibitors of Alzheimer's disease. J Mol Model. 2018;24(7):151.
Hu, X. M., Dong, W., Cui, Z. W., Gao, C. Z., Yu, Z. J., Yuan, Q., & Min, Z. L. (2018). In silico identification of AChE and PARP-1 dual-targeted inhibitors of Alzheimer's disease. Journal of Molecular Modeling, 24(7), 151. https://doi.org/10.1007/s00894-018-3696-6
Hu XM, et al. In Silico Identification of AChE and PARP-1 Dual-targeted Inhibitors of Alzheimer's Disease. J Mol Model. 2018 Jun 5;24(7):151. PubMed PMID: 29869722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In silico identification of AChE and PARP-1 dual-targeted inhibitors of Alzheimer's disease. AU - Hu,Xia-Min, AU - Dong,Wei, AU - Cui,Zhi-Wen, AU - Gao,Cheng-Zhi, AU - Yu,Zhi-Jun, AU - Yuan,Qiong, AU - Min,Zhen-Li, Y1 - 2018/06/05/ PY - 2017/10/29/received PY - 2018/05/23/accepted PY - 2018/6/6/entrez PY - 2018/6/6/pubmed PY - 2018/10/20/medline KW - AChE KW - Alzheimer’s disease KW - Molecular dynamics KW - PARP-1 KW - Virtual screening SP - 151 EP - 151 JF - Journal of molecular modeling JO - J Mol Model VL - 24 IS - 7 N2 - Alzheimer's disease (AD) is a chronic neurodegenerative disease of the elderly that seriously affects the quality of life and the life expectancy of those affected. There is, as yet, no effective drug treatment of AD, although several acetylcholinesterase (AChE) inhibitors and a glutamate antagonist can provide relief from its symptoms. Recent studies have indicated that the overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) may promote nerve cell death in the brains of AD patients, implying that PARP-1 inhibition may have therapeutic value for the treatment of AD. Therefore, it is important to investigate novel agents with both AChE- and PARP-1-inhibitory bioactivities. In this study, the structure-based virtual screening of PARP-1 inhibitors was performed to search for potential agents with high affinities for AChE. The dynamic stability of the selected AChE-ligand complexes was investigated by molecular dynamics (MD) simulation. Two compounds, CID57390505 and CID71605390, showed high affinities for and stability in complex with AChE in docking and MD simulations. Thus, our in silico research identified two compounds with AChE and PARP-1 dual-targeted activities, indicating that this technique could aid attempts to develop more potent agents against AD. SN - 0948-5023 UR - https://www.unboundmedicine.com/medline/citation/29869722/In_silico_identification_of_AChE_and_PARP_1_dual_targeted_inhibitors_of_Alzheimer's_disease_ DB - PRIME DP - Unbound Medicine ER -