Computational Evidence to Inhibition of Human Acetyl Cholinesterase by Withanolide A for Alzheimer Treatment
Alzheimer’s disease (AD), a neurodegenerative disorder, is the most common cause of dementia. So far only five drugs have been approved by US FDA that temporarily slow worsening of symptoms for about six to twelve months. The limited number of therapeutic options for AD drives the exploration of new drugs. Enhancement of the central cholinergic function by the inhibition of acetylcholinesterase is a prominent clinically effective approach for the treatment of AD. Recently withanolide A, a secondary metabolite from the ayurvedic plant Withania somnifera has shown substantial neuro-protective ability. The present study is an attempt to elucidate the cholinesterase inhibition potential of withanolide A along with the associated binding mechanism. Our docking simulation results predict high binding affinity of the ligand to the receptor. Further, long de novo simulations for 10 ns suggest that ligand interaction with the residues Thr78, Trp81, Ser120 and His442 of human acetylcholinesterase, all of which fall under one or other of the active sites/subsites, could be critical for its inhibitory activity. The study provides evidence for consideration of withanolide A as a valuable small ligand molecule in treatment and prevention of AD associated pathology. The present information could be of high value for computational screening of AD drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of human acetylcholinesterase would further enhance the potential of such analysis in understanding the molecular interaction basis between ligand and receptor.
Key words: Acetylchloinesterase; Withanolide A; Docking; Simulations; Withania.
This article can be cited as:
A. Grover, A. Shandilya, V. Agrawal, V.S. Bisaria, D. Sundar. Computational Evidence to Inhibition of Human Acetyl Cholinesterase by Withanolide A for Alzheimer Treatment J. Biomol Struct Dyn 29(4), 651-662 (2012).
1Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas,
New Delhi 110016, India
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