Structural and molecular features of acetylcholinesterase targeting small molecules: leveraging in silico tools to combat Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative condition that leads to the gradual decline of neuronal cells. Despite significant interest and investment, complete prevention or treatment for AD and related dementia is still limited. The human acetylcholinesterase (hAChE) enzyme is a promising target for combating AD as it plays a crucial role in metabolising the neurotransmitter acetylcholine, which is essential for cognitive function and memory. The present study employed a multi-step approach, beginning with molecular docking to virtually screen 73 531 compounds from the PubChem library. Subsequently, we used Glide extra precision molecular docking to narrow down the list to three compounds (PubChem CID: 73058259, 141100002, and 44285707). The pharmacological and ADMET properties of the top three compounds were determined using multiple tools. The molecular dynamics (MD) simulation study at 500 ns revealed that all the ligands formed stable complexes with AChE. The trajectories of the ligands were stable, similar/better to the reference compound (donepezil), and identified compounds have drug-like features. This study presents the unique findings of structural and molecular features of new hAChE inhibitors and their dynamics, which have not been studied before. These insights could pave the way for developing more effective treatments for neurological conditions.