A CoMFA study of enantiomeric organophosphorus inhibitors of acetylcholinesterase
In a previous paper, presented by P. Bernard et al. [1], an automated docking was performed for stereospecific and quasi-irreversible organophosphorus acetylcholinesterase (AChE) inhibitors. In this study twelve chiral inhibitors, 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 organophosphorus compounds. The selected bioactive conformations derived from the docking procedure were used to establish a three dimensional model by means of the Comparative Molecular Field Analysis (CoMFA) method. In contrast to the conventional CoMFA studies, the compounds were not fitted to a reference compound but taken in their protein-based alignments derived from the docking study. For validation purposes, the established CoMFA model was then applied to another series of 24 organophosphorus compounds whose AChE inhibitory activity data were measured in different experimental conditions. A good correlation between predicted and experimental activity data shows that the model is robust and can also be extended to AChE inhibitory activity data measured on another acetylcholinesterase and/or at different incubation times and pH level.
comfa organophosphorus compounds irreversible ache inhibitors