- 作者: Shin-Hua Lu; Josephine W. Wu; Hsuan-Liang Liu; Jian-Hua Zhao; Kung-Tien Liu; Chih-Kuang Chuang; Hsin-Yi Lin; Wei-Bor Tsai; Yih Ho
- 作者服務機構: 1Graduate Institute of Biotechnology, National Taipei University of Technology, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
Background: Alzheimer’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.
Methods: In 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.
Results: The 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.
Conclusions: The information gained from this study may assist in the discovery of
potential AChE inhibitors that are highly selective for its dual binding sites. - 中文關鍵字: --
- 英文關鍵字: --