Potential alternatives to current cholinesterase inhibitors: an in silico drug repurposing approach

Abstract

Acetylcholinesterase/Butyrylcholinesterase inhibitors are considered an effective method for treating Alzheimer’s disease (AD). In this current work, we have computationally analyzed 11 new small molecule drugs used in various neurological diseases and Donepezil, a known inhibitor of acetylcholinesterase, as a positive control. We investigated these drugs for possible fundamental interactions with acetylcholinesterase and butyrylcholinesterase as both are critical in the pathophysiology of Alzheimer’s disease. We have selected FDA approved compounds for repurposing as possible inhibitors of these enzymes and novel therapeutic option for Alzheimer’s disease. We selected the top two molecules for each protein for their binding energies, interactions, and Donepezil, the most commonly used drug for AD treatment. Molecular simulation and dynamics studies of the top 2 drugs in each case and free energy analysis helped us reach further conclusions about the best possible drugs for repurposing. Brexipirazole and Deutetrabenazine produce encouraging results as butyrylcholinesterase and acetylcholinesterase inhibitors, respectively.

Keywords:

• Drug development
• acetylcholinesterase
• acetylcholinesterase inhibitors
• cholinergic hypothesis
• molecular docking

Acknowledgement

DK acknowledges research fellowship by IIT (BHU) Varanasi. The infrastructure support and the resources provided by DST funded I-DAPT Hub Foundation, IIT BHU [DST/NMICPS/TIH11/IIT(BHU)2020/02] and PARAM Shivay Facility under the National Supercomputing Mission, Government of India at the Indian Institute of Technology, Varanasi are gratefully acknowledged.

Disclosure statement

No potential conflict of interest was reported by the author(s).