On the Mechanisms of Anticholinesterase Action of Organophosphorus Inhibitors (OPI)

The models of 10 various ChEs active center serine hydroxyl phosphorylation by 55 different OPI molecules were examined. The hydroxyl attack occurs from the side of phosphorus atom opposite to the breaking bond. So the efficiency of such reactions should depend on the spatial accessibility of the phosphorus atom for the attacking agent. To obtain the quantitative estimates of the accessibility of the phosphorus atom face, conformational flexible inhibitors were taken into account. Using the molecular mechanics method all minimum-energy conformations (conformers) of OPI series with different phosphoryl and leaving group structures were calculated, the accessibility of the phosphorus atom in every conformer was determined. To estimate the accessibility of the phosphorus atom for the attacking agent a cylinder of definite radius was drawn, its axis coinciding with the extension of the breaking bond and one of its basses touching van der Waals surface of the phosphorus atom at the face opposite the breaking bound while the other being in infinity. The conformer was considered to be accessible in the chosen direction unless the center of any atom fell within the cylinder. To evaluate a possible correlation between conformational characteristics of inhibitors and their anti-enzyme activities the population of conformers was calculated.