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Quantum chemical calculations for understanding and predicting toxicity. II. The phosphorylation step in the inhibition of ache by organophosphorus anticholinesterases
Author(s) -
Lewchenko Victor,
Hariharan P. C.,
Koski Walter S.,
Kaufman Joyce J.
Publication year - 2009
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560220725
Subject(s) - acetylcholinesterase , chemistry , aché , computational chemistry , stereochemistry , quantum chemical , molecule , phosphorylation , enzyme , organic chemistry , biochemistry
Abstract 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].