Molecular docking, ADME/toxicity, and VMD–RDG investigation of secondary amines as acetylcholinesterase inhibitors

Secondary amines are considered promising inhibitors of acetylcholinesterase (AChE), an important therapeutic target in the symptomatic treatment of Alzheimer’s disease. In this study, a computational strategy combining molecular docking, ADME/toxicity prediction, and VMD–RDG analyses was applied to study the behavior of 1a–12a compounds. The RDG analysis revealed that molecular stability is mainly governed by dispersion interactions, while localized hydrogen bonding interactions and steric effects associated with substituent arrangement also contribute significantly. Pharmacokinetic predictions suggested favorable drug-like properties, including good oral bioavailability, high gastrointestinal absorption, blood-brain barrier permeability and compliance with Lipinski’s rules. The docking studies performed indicated that compounds 6a, 8a and 9a may be related to AChE, tends that compounds 5a and 8a seemed to offer a more balanced combination between predicted activity and safety. Interaction analysis has also shown that hydrogen bonds, π-π stacking and hydrophobic contacts all contribute to the stabilization of ligand-enzyme complexes. Overall, the compounds 5a and 8a seem to deserve to be explored more in depth through molecular dynamics simulations and experimental validation as potential AChE inhibitors.