The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies
Open Access
- 21 January 2011
- journal article
- Published by Springer Science and Business Media LLC in Journal of Biomedical Science
- Vol. 18 (1), 8
- https://doi.org/10.1186/1423-0127-18-8
Abstract
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. 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. 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. The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.Keywords
This publication has 48 references indexed in Scilit:
- Induced‐fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure‐based drug designProtein Science, 2008
- Benchmarking Sets for Molecular DockingJournal of Medicinal Chemistry, 2006
- Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortexNeurobiology of Aging, 2003
- The price of innovation: new estimates of drug development costsJournal of Health Economics, 2003
- Cheminformatics Analysis of Organic Substituents: Identification of the Most Common Substituents, Calculation of Substituent Properties, and Automatic Identification of Drug-like Bioisosteric GroupsJournal of Chemical Information and Computer Sciences, 2002
- Pathways of ligand clearance in acetylcholinesterase by multiple copy samplingJournal of Molecular Biology, 2000
- The Protein Data BankNucleic Acids Research, 2000
- Structure of acetylcholinesterase complexed with (−)‐galanthamine at 2.3 Å resolutionFEBS Letters, 1999
- Acetylcholinesterase Accelerates Assembly of Amyloid-β-Peptides into Alzheimer's Fibrils: Possible Role of the Peripheral Site of the EnzymeNeuron, 1996
- CHARMM: A program for macromolecular energy, minimization, and dynamics calculationsJournal of Computational Chemistry, 1983