MD Simulations, DFT and Molecular Docking Studies of Schiff Base–Derived Heterocycles as Potent BuChE Inhibitors for Alzheimer's Disease

ABSTRACT Butyrylcholinesterase (BuChE) must be considered a critical target for effective Alzheimer's disease (AD) therapy. This investigation utilises in silico techniques to assess the cholinesterase inhibition profiles of a series of 32 Schiff base–derived azetidinone heterocycles. The program Schrödinger was used to perform in silico procedures, including docking, MMGBSA, molecular dynamics (MD) simulation and pharmacophore modelling investigations. Compounds A28, A26 and A27 exhibited exceptional docking scores against butyrylcholinesterase, and MMGBSA calculations assessed further binding energy. Meanwhile, the stability of the A28, A26 and A27 complexes with 6SAM was evaluated through MD simulations, which confirmed that the A28_6SAM complex exhibited greater stability than the others, thereby supporting the overall stability of the ligand–target interactions. According to the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies, compound A28 was determined to be electrically stable in density functional theory (DFT) investigations. Analysis of pharmacophore modelling revealed structural elements necessary for inhibition. These results demonstrate the potential of azetidinone heterocycles as potent butyrylcholinesterase inhibitors. All compounds were predicted to have anti‐Alzheimer potential using the prediction of activity spectra for substances (PASS) algorithm. After evaluating additional expected targets for A28, reverse docking with these newly anticipated targets was also done for confirmation. These findings underscore the utility of in silico methodologies in the rational design and identification of novel butyrylcholinesterase inhibitors as prospective healing agents for AD.