The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies

Journal of Biomedical Science

Research

Kung-Tien Liu¹  Jian-Hua Zhao¹  Wei-Bor Tsai²  Hsin-Yi Lin³  Josephine W Wu³  Shin-Hua Lu³  Hsuan-Liang Liu⁴  Chih-Kuang Chuang⁵  Yih Ho⁶ 

[1] Chemical Analysis Division, Institute of Nuclear Energy Research, 1000, Wunhua Rd, 32546, Longtan Township, Taoyuan County, Taiwan;Department of Chemical Engineering, National Taiwan University, 1 Sec. 4 Roosevelt Rd, 106, Taipei, Taiwan;Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd, 10608, Taipei, Taiwan;Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd, 10608, Taipei, Taiwan;Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd, 10608, Taipei, Taiwan;Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd, 10608, Taipei, Taiwan;Division of Genetics and Metabolism, Department of Medical Research, Mackay Memorial Hospital, 92, Sec. 2, Chung-Shan N. Rd, 10449, Taipei, Taiwan;College of Medicine, Fu-Jen Catholic University, 510 Chung Cheng Rd, 24205, Hsinchuang, Taipei County, Taiwan;School of Pharmacy, Taipei Medical University, 250 Wu-Hsing St, 110, Taipei, Taiwan;

关键词: Molecular Docking;    Virtual Screening;    Pharmacophore Model;    AChE Inhibitor;    Pharmacophore Feature;   

DOI  :  10.1186/1423-0127-18-8

 received in 2010-11-15, accepted in 2011-01-21,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundAlzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD.MethodsIn this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5) program based on a set of known AChE inhibitors.ResultsThe best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R2 = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site.ConclusionsThe information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.

【 授权许可】

Unknown   
© Lu et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.