Investigation of cholinergic inhibition by donepezil-rimegepant hybrids in alzheimer’s disease: An in silico study

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that causes damage to brain cells, resulting in memory loss, thinking, and executive skills. AD is widely recognized as a most prevalent type of dementia that occurs in elder people. Although few medications like donepezil are available to treat AD, a new and effective drug is the need of the hour. Hence, in the present study, an in silico approach is used to investigate the cholinergic inhibition by donepezil-rimegepant hybrids. Inspired by the structure of donepezil and rimegepant, Donepezil-Rimegepant (DR) hybrids are generated using a hybridization-based design strategy. Their biological activity towards acetylcholinesterase, (AChE) butyrylcholinesterase (BuChE) and amyloid β (Aβ) peptides is investigated using computational techniques such as DFT and molecular docking. Our DFT calculations indicate that the DR13 is highly stable than the other hybrids considered in this study. Similarly, our molecular docking study revealed that DR13 has strong interactions with AChE, BuChE, and Aβ peptide. While considering donepezil and the rimegepant region in DR hybrid, later has strong binding with the protein targets considered in this study. This is due to the presence of two F atoms in the benzyl region of rimegepant. These halogens form strong noncovalent interactions with the amino acid residues in the protein targets. Therefore, based on our in silico studies DR13 is proposed as a good candidate molecule for designing a new drug against AD.