Acetylcholine, a neurotransmitter released into nerve terminals, has to be broken down as quickly as it is released. About 25,000 acetylcholine molecules are hydrolysed per second by acetylcholinesterase, an enzyme with very high activity.
But a loss of cholinergic activity has been found in Alzheimer’s disease – a disease marked by forgetfulness of recent events, typically among the elderly. So, a therapeutic strategy, to reduce the breakdown of acetylcholine and to compensate for the reduced release, is to inhibit the enzyme’s activity.
There are many plant metabolites that may have activity against acetylcholine esterase. But identifying them by trial and error is laborious and time consuming.
A team of scientists from the Manipur University, the Central University of South Bihar, the King Saud University and the University of Delhi came up with an alternative strategy: a computer-aided method to identify medicinal plants with activity against acetylcholinesterase.
Based on the biochemical structure of donepezil, a dual binding inhibitor of acetylcholinesterase, they designed a pharmacophore, the part of a molecule responsible for a specific pharmacological interaction.
The team had constructed a natural product database during their previous work. Using a query based on the biochemical structure of donepezil, they searched for molecules with similar pharmacophores in their database. And they ranked the molecules retrieved according to the root mean square deviation from the query and the target pharmacophore features. Thus they selected twelve compounds.
The team then conducted molecular docking studies on those compounds to check for characteristic dual docking properties similar to donepezil. They ranked the molecules according to the docking score and, after manual examination of the docking patterns, selected five for further analysis.
Two molecules out of the five were already reported to have acetylcholinesterase inhibitory activity. The remaining three were from leaves of Dioscorea bulbifera, Alocasia macrorrhizos and rhizomes of Alpinia officinarum.
The scientists followed up with in-vitro studies. They tested the extracts of the three medical plants for acetylcholinesterase inhibitory activity. The enzyme breaks acetylthiocholine into acetate and thiocholine, and thiocholine is easily detected with a chemical that turns the solution yellow. Thus they could quantify the inhibition caused by the plant extracts at different concentrations.
The compound from Dioscorea bulbifera and Alpinia officinarum showed moderate inhibitory activity on acetylcholinesterase.
Dioscorea bulbifera and Alpinia officinarum. Images by Jeevan Jose and Luc Viatour,
via Wikimedia Commons
“A combination of databases of medicinal plants and in silico methods for drug discovery and confirmation by in vitro methods have speeded up the process to half way. Now this has to be followed up by animal studies and human clinical trials”, says Angamba Potshangbam, Manipur University.
Alzheimer’s disease affects about ten million people worldwide – many of them in resource-poor settings. Even the poor can access alternative treatments based on natural products.
Dioscorea bulbifera needs to be treated before consuming to remove toxic constituents. But Alpinia officinarum is used in cooking and can serve as a nutraceutical for Alzheimers.
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