Asghar_2026_PLoS.One_21_e0346177

Alzheimer's Disease (AD), the dominant form of dementia that evolves with age, involves several mechanisms by which it progresses. The cholinergic hypothesis proposes that the activity of Acetylcholinesterase (AChE) causes the decline of cholinergic neurotransmission, which leads to Alzheimer's Disease. Considerable studies are being conducted to determine the best AChE inhibitor. This study evaluated 40 phytocompounds from the Astragalus zederbaueri plant as potential AChE inhibitors for Alzheimer's disease. The analysis of the phytochemicals was conducted using the control drug donepezil (co-crystallized ligand) through various computational tools and biological databases for docking, visualization, and simulation. The findings of our research showed that the key ligands according to the docking analysis were Rutin (AZ-29), Kaempferol-3-O-rutinoside (Nicotiflorin) (AZ-32), and Isoquercitrin (AZ-28); nevertheless, it was found that Rutin played the most effective role of an anti-AChE compound with an exceptional binding affinity of -15.043 kcal/mol. TRP341 and TYR286 were key amino acid residues in hydrogen bonds and Pi-Pi stacking interactions, respectively. The results of pharmacokinetic and toxicological analyses of these compounds were within the acceptable range. Moreover, the molecular dynamics simulation confirmed the stability of the complexes. Our findings suggest a novel phytochemicals from Astragalus zederbaueri for Alzheimer's disease, paving the way for further experimental validation and drug development.