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 neurodegeneration,
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.
[18F]Amylovis as a Potential PET Probe for β-Amyloid Plaque: Synthesis, In Silico, In vitro and In vivo Evaluations
