Conformational Analysis and Docking Study of Potent Acetylcholinesterase Inhibitors Having a Benzylamine Moiety

Abstract

A conformational analysis and docking study of nitrophenoxyalkylbenzylamine derivatives with inhibitory activities against acethylcholinesterase was carried out in an attempt to analyze their structure-activity relationships based on the enzyme-inhibitor interaction. First, stable conformers of the inhibitors alone were obtained from the conformational analysis by molecular dynamics. Next, a docking study of the inhibitors into the ligand binding site was performed. Among the resulting stable complex structures, it was found that in the case of the two stereoisomers with a 7-membered ring, the more active one of the two formed a much more stable complex structure. On the other hand, complex structures with comparable energies were obtained for both stereoisomers that had no 7-membered ring and showed similar inhibitory activities. Lastly, structural features of the complex models of a series of inhibitors with side chains of different lengths were evaluated and corresponded well to their inhibitory activities.