Automated docking of 82 N-benzylpiperidine derivatives to mouse acetylcholinesterase and comparative molecular field analysis with 'natural' alignment

Automated docking and three-dimensional Quantitative Structure-Activity Rel ationship studies (3D QSAR) were performed for a series of 82 reversible, c ompetitive and selective acetylcholinesterase (AChE) inhibitors. The sugges ted automated docking technique, making use of constraints taken from exper imental crystallographic data, allowed to dock all the 82 substituted N-ben zylpiperidines to the crystal structure of mouse AChE, because of short com putational times. A 3D QSAR model was then established using the CoMFA meth od. In contrast to conventional CoMFA studies, the compounds were not fitte d to a reference molecule but taken in their `natural' alignment obtained b y the docking study. The established and validated CoMFA model was then app lied to another series of 29 N-benzylpiperidine derivatives whose AChE inhi bitory activity data were measured under different experimental conditions. A good correlation between predicted and experimental activity data shows that the model can be extended to AChE inhibitory activity data measured on another acetylcholinesterase and/or at different incubation times and pH l evel.