期刊
CURRENT ALZHEIMER RESEARCH
卷 16, 期 2, 页码 116-127出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205016666181212155147
关键词
Alzheimer's disease; molecular docking; molecular dynamics simulations; neurotoxicity; protein-ligand interactions; primary neuronal culture
资金
- Jaypee University of Information Technology (JUIT)
- ICMR [BIC/12(33)/2012]
Background: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer's disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer 'disease-modifying drugs'. Methods: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. Results: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurode-generation, which other molecules, including donepezil and begacestat, failed to do. Conclusion: Quercetin and caffeine have the potential as disease-modifying drugs and may find application in the management of neurological disorders such as AD.
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