Quantum chemical calculations for understanding and predicting toxicity. II. The phosphorylation step in the inhibition of ache by organophosphorus anticholinesterases

The first step in the inhibition of acetylcholinesterase (AChE) by organophosphorus anticholinesterases is formation of the organophosphorous molecule‐AChE complex. In the first paper of this series it was shown that the first step can be modeled well by the use of three‐dimensional electrostatic molecular potential contour maps around the P compound. The second phosphorylation step of the mechanism by which organophosphorous anticholinesterases of the general formula inhibit AChE is related to the acidity of X and to the bond strength of the P—X bond. For a series of compounds, aryl N ‐methyl methyl phosphoramidates, in which the P—X bond is constant, this paper shows that the quantum chemically calculated P‐O total overlap populations (TOPs) correlate the experimental log I 50 for inhibition of AChE over four orders of magnitude with correlation coefficients of 0.96 [ r 2 : TOP 0.9581; (TOP) 1/2 0.9614].