Alzheimer's disease research by screening inhibitory molecules targeting acetylcholinesterase
2016
Amrita University, Kochi, India
Cognitive decline in Alzheimer's disease might be led by dysregulation of acetylcholine, known as the cholinergic hypothesis. For this reason, several treatment strategies for this neurodegenerative disorder are based on targeting the inhibition of acetylcholinesterase, for example with donepezil, but which can cause severe side effects. In this study, a 3D-pharmacophore model using specific inhibitors was used for sequential virtual screening from small-molecule databases. Five molecules, selected based on their docking scores and pharmacokinetic properties, were then tested against the crystal structure of human acetylcholinesterase to reveal their binding mechanisms. After confirming their ADMET profiles, these molecules were subjected to Ellman's assay to assess their inhibitory activity, which for three of the five selected molecules was shown to be weaker than Donepezil. Here, the researchers propose a methodology that can lead to the discovery of existing molecules that can have better inhibitory activity of acetylcholinesterase than those used currently in clinical applications.
Integration of common feature pharmacophore modeling and in vitro study to identify potent AChE inhibitors
C Gopi Mohan, Krishnakumar N Menon
Added on: 08-15-2021
[1] https://link.springer.com/article/10.1007/s00044-016-1716-6[2] https://data.jrc.ec.europa.eu/dataset/a8fd26ef-b113-47ab-92ba-fd2be449c7eb
