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

Shin-Hua Lu,Wei-Bor Tsai,Kung-Tien Liu,Hsin-Yi Lin,Hsuan-Liang Liu,Chih-Kuang Chuang,Yih Ho,Jian-Hua Zhao,Josephine W Wu

doi:10.1186/1423-0127-18-8

Abstract

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.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people
It has been found that AChE is involved in pathogenesis of AD through a secondary noncholinergic function associated with its peripheral anionic site
The work presented in this study shows that a set of compounds along with their activities ranging over several orders can be used to generate a good pharmacophore model, which in turn can be utilized to successfully predict the activity of a wide variety of chemical scaffolds

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. Recent findings support the enzyme’s role in mediating the processing and deposition of Ab peptide by colocalizing with Ab peptide deposits in the brain of AD patients and promoting Ab fibrillogenesis through the formation of stable AChE-Ab complexes The formation of these complexes promotes Ab aggregation as an early event in the neurodegenerative cascade of AD [5,6] and results in cognitive impairment in doubly transgenic mice expressing human amyloid precursor protein (APP) and human AChE [7,8]. Based on these new findings, the recent design of novel classes of AChE inhibitors as therapeutic intervention for AD has been shifted toward blocking the peripheral site of AChE, the Ab recognition zone within the enzyme [9], thereby affect the AChE-induced Ab aggregation and modulate the progression of AD

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