Interactions-guided blueprint of acetylcholinesterase binding: A review on structural and molecular determinants

Acetylcholinesterase (AChE) remains one of the most extensively studied enzymatic targets in neuropharmacology due to its central role in cholinergic neurotransmission and its relevance in symptomatic cognitive disorders, toxicology, and neuromodulation. AChE terminates cholinergic neurotransmission by hydrolyzing acetylcholine, and its inhibition provides clinically established symptomatic relief in cholinergic dysfunction-associated pathological conditions. For any newly discovered ligand, the precise target binding mode often remains challenging, and unfortunately, the binding patterns of most reported compounds have not been experimentally resolved. However, recent advances in structural biology, particularly biomolecular crystallographic structures deposited in the Protein Data Bank, have significantly enriched our understanding of the active site of AChE and its interactions with diverse chemical classes of ligands. To this end, this article presents a comprehensive systematic analysis of 202 AChE-ligand complexes (1993-2025) since the first breakthrough, categorizing ligands by their core scaffolds or functional groups, including decamethonium, huprine, galanthamine, quinoline, huperzine, tacrine, pyridinium, sulphonamide, and quaternary amine derivatives. Crucial interactions with core residues of the binding pocket, such as hydrogen bonding, cation-π, carbon-π, π-π stacking, and van der Waals forces, primarily associated with the stabilization of AChE-ligand complexes, are discussed involving organisms like Tetronarce californica, Homo sapiens, and Mus musculus, emphasizing their role in inhibitory potency. All ligands are further evaluated using Lipinski's Rule of Five filters to assess drug-likeness and identify optimization strategies for improved bioavailability and pharmacokinetics. By integrating structural insights with ligand features, this article provides a comprehensive framework for the rational design and optimization of next-generation AChE modulators across neurological and toxicological conditions.