Structure-based Design and Computational Evaluation of Spiropyrrolidine Derivatives as Novel Acetylcholinesterase Inhibitors for Alzheimer’s Disease

Abstract

Acetylcholinesterase (AChE; E.C. 3.1.1.7) is a key enzyme involved in cholinergic neurotransmission, catalyzing the hydrolysis of acetylcholine (ACh). Reduced ACh levels are associated with Alzheimer's disease (AD), making AChE inhibition an effective therapeutic strategy. Structurally, AChE possesses a deep active site gorge with peripheral and catalytic subsites, including the catalytic triad (Ser203, Glu334 and His447), which plays a crucial role in enzyme activity. In the present study, the synthesized pyrrolopiperazine-derived spiropyrrolidine derivatives were evaluated as potential AChE inhibitors using in silico approaches. Molecular docking, induced fit docking (IFD) and conformational analyses were performed to investigate ligand–protein interactions and binding efficiency. The results were compared with dihydrotanshinone I (DHI), a known peripheral site inhibitor. Furthermore, ADME/Tox predictions were carried out to assess pharmacokinetic and safety profiles. The findings revealed that several synthesized spiropyrrolidine compounds exhibited favorable binding interactions with key active site residues and showed promising drug-like properties. These compounds may serve as potential leads for the development of novel AChE inhibitors and may provide new insights for therapeutic strategies in Alzheimer's disease.