Identifying Donepezil‐Like Compounds Against Acetylcholinesterase Using Molecular Docking, Dynamic Simulation, ADMET, and PCA: Therapeutic Management of Alzheimer’s Disease

Alzheimer’s disease (AD) is a significant concern in the elderly, characterized by impaired cholinergic transmission,decreased choline acetyltransferase activity and increased acetylcholinesterase (AChE) activity, resulting in reduced acetylcholine levels. First‐generation AChE inhibitors (AChEIs), including tacrine, and second‐generation agents, such as donepezil, galantamine, and rivastigmine, offer only limited symptomatic relief. More comprehensive drug treatment plans are in demand. AChE, crucial for acetylcholine regulation, is a key focus due to its altered activity in AD. Enhancing cholinergic activity via AChEIs remains a viable strategy, exemplified by Donepezil. However, the effectiveness of Donepezil as an AD therapeutic is limited by various side effects and solubility issues. In this study, we used a structure‐guided strategy to screen Donepezil analogs for the identification of potential compounds for AChE inhibition. We identified two Donepezil‐like compounds (PubChem CIDs 14553578 and 19820656) that show a higher predicted binding affinity and stability with AChE in our in silico workflow compared with Donepezil. These findings are computational and hypothesis‐generating; experimental biochemical and pharmacological validation, such as in vitro enzymatic IC 50 determinations, cellular ADME/Tox profiling, and in vivo studies, will be required to confirm biological activity and therapeutic potential.