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 IC₅₀ determinations, cellular ADME/Tox profiling, and in vivo studies, will be required to confirm biological activity and therapeutic potential.