A CoMFA study of enantiomeric organophosphorus inhibitors of acetylcholinesterase

In a previous paper, presented by P. Bernard et al. [1], an automated docki ng was performed for stereospecific and quasi-irreversible organophosphorus acetylcholinesterase (AChE) inhibitors. In this study twelve chiral inhibi tors, corresponding to six enantiomeric pairs, each with a phosphorus atom as a stereocenter, were docked to the crystal structure of mouse AChE. Then , the automated docking procedure was extended to a series of 35 organophos phorus compounds. The selected bioactive conformations derived from the doc king procedure were used to establish a three dimensional model by means of the Comparative Molecular Field Analysis (CoMFA) method. In contrast to th e conventional CoMFA studies, the compounds were not fitted to a reference compound but taken in their protein-based alignments derived from the docki ng study. For validation purposes, the established CoMFA model was then app lied to another series of 24 organophosphorus compounds whose AChE inhibito ry activity data were measured in different experimental conditions. A good correlation between predicted and experimental activity data shows that th e model is robust and can also be extended to AChE inhibitory activity data measured on another acetylcholinesterase and/or at different incubation ti mes and pH level.