Molecular Docking Analysis and Comparative Evaluation of Phytochemical Compounds Against Acetylcholinesterase and Butyrylcholinesterase Enzymes in Alzheimer's Disease
Abstract
Background: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) regulate cholinergic neurotransmission and remain relevant targets for symptomatic treatment and ligand discovery in Alzheimer's disease. This study comparatively screened 16 phytochemicals from six medicinal plants against human AChE and BChE. Methods: Human AChE (PDB ID: 4EY7) and BChE (PDB ID: 6ESY) structures were prepared in AutoDockTools. Docking was conducted in AutoDock 4.2 using the Lamarckian genetic algorithm, 100 independent runs, and target-specific grids centred on the crystallographic binding pockets. Donepezil and galantamine were used as pharmacological comparators for AChE and BChE, respectively. Predicted physicochemical and drug-likeness properties were assessed with SwissADME. Results: Asiatic acid showed the most favourable predicted binding energy for AChE (−11.79 kcal/mol), close to donepezil (−11.65 kcal/mol). Withanolide A ranked first for BChE (−10.06 kcal/mol), followed by asiatic acid (−9.65 kcal/mol), madecassic acid (−9.12 kcal/mol), and asiaticoside (−9.08 kcal/mol), compared with galantamine (−6.74 kcal/mol). Interaction mapping suggested that asiatic acid occupied the catalytic gorge of both enzymes and formed hydrogen-bond, aromatic, and hydrophobic contacts with residues surrounding the binding pockets. Most compounds met Lipinski criteria; however, several highly ranked ligands were predicted not to cross the blood–brain barrier. Conclusions: The docking results identify asiatic acid, withanolide A, rosmarinic acid, and madecassic acid as candidates for experimental cholinesterase testing. Because docking scores do not establish biochemical inhibition or clinical efficacy, enzyme assays, selectivity testing, pharmacokinetic studies, and molecular-dynamics validation are required
Keywords
Alzheimer's disease, acetylcholinesterase, butyrylcholinesterase, AutoDock, phytochemical, drug-likeness
Ethical Statement
Not applicable. This study was based entirely on in silico analyses using publicly available molecular structure data and did not involve human participants, animals, biological samples, or personally identifiable information.
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