Molecular Docking and ADMET Analysis of Selected Polyphenols Targeting Acetylcholinesterase: An In Silico Approach

Alzheimer's disease (AD) is a multifactorial, progressive neurodegenerative disorder, primarily caused by disorders in the cholinergic system. Inhibition of the acetylcholinesterase (AChE) enzyme forms the basis of current symptomatic treatment. The aim of this study is to investigate the potential inhibitory effects of several different polyphenols, whose biological activities are known in the literature, on AChE using in silico methods. In this study, molecular docking simulations were performed using the crystal structure of the AChE enzyme (PDB code: 4EY7) and the structures of selected natural compounds and the reference drug donepezil. The binding affinities (kcal/mol) and binding modes of the compounds to the enzyme's active site were determined using AutoDock Vina software. In addition, in silico ADMET (Absorption, Distribution, Metabolism, Elimination, Toxicity) analyses were performed using ADMETlab 3.0 to predict the drug similarity, pharmacokinetic, and toxicological profiles of these compounds. Molecular docking analyses revealed that the reference drug donepezil showed the highest binding affinity (-11.9 kcal/mol), followed by naturally occurring compounds such as rosmarinic acid (-10.5 kcal/mol) and apigenin (-10.4 kcal/mol). Structural analyses showed that all compounds with strong affinity, like donepezil, exhibited dual-site inhibitory behavior, interacting simultaneously with both the catalytic active site and the peripheral anionic site of AChE. ADMET analyses demonstrated that all compounds studied conformed to Lipinski's rule and possessed generally acceptable pharmacokinetic and toxicity profiles. The results indicate that the polyphenols studied, particularly rosmarinic acid and apigenin, are promising AChE inhibitor candidates in the treatment of AD, exhibiting high affinity and dual-site binding potential. These findings form the basis for in vitro and in vivo validation studies for the development of natural compounds.