Relationships Between Activity of Organophosphorus Inhibitors of Acetylcholinesterase and Accessibility of Phosphorus Atom as Estimated by Molecular Mechanics Calculations

Irreversible inhibition of acetylcholinesterase (AChE) by organophosphorus compounds is believed to be due to phosphorylation of serine hydroxyl in the enzyme active center (Cohen, Oosterbaan, 1963). The attack by the hydroxyl may occur from the different faces of phosphorus atom (Berman and Decker, 1989). The efficiency of these reactions should depend on sterical accessibility of the phosphorus atom for the attacking agent. In particular, low activity of some inhibitors may be due to low accessibility of their phosphorus atom in the reaction with the enzyme. To obtain quantitative estimates of the accessibility of different faces of the phosphorus atom, conformational flexibility of inhibitors should be taken into account. In this work, using molecular mechanics method, we have calculated all minimum-energy conformations (conformers) of 15 organophosphorus inhibitors with nitro-phenyl and S-ethylthioethyl leaving groups and different structure of phosphoryl moiety, determined the accessibility of the phosphorus atom in every conformer, and compared anti-AChE efficiency of the compounds with the total population of those conformers which have accessible phosphorus atom.