Reactivation of model cholinesterases by oximes and intermediate phosphyloximes: A computational study

Department of Chemistry, The Ohio State University, 100 W. 18th Avenue, Columbus, OH 43210 USA.
Chemico-Biological Interactions (Impact Factor: 2.58). 06/2008; 175(1-3):187-91. DOI: 10.1016/j.cbi.2008.05.006
Source: PubMed


Phosphyloximes (POX) are generated upon the reactivation of organophosphorus (OP)-inhibited cholinesterases (ChEs) by pyridinium oximes. These POXs are known to be potent inhibitors of the ChEs following reactivation. However, they can also decompose to give an OP derivative and a cyano derivative of the oxime when a base abstracts the benzylic proton. Using density functional theory, thermodynamic properties were calculated for the reactivation and decomposition pathways of three different oximes (2-PAM, 3-PAM and 4-PAM) with six different OPs (cyclosarin, paraoxon, sarin, tabun, VR and VX). For reactivation purposes, 2-PAM is predicted to be more efficient than 3- and 4-PAM. Based on atomic charges and relative energies, 2-POXs were found to be more inclined towards the decomposition process.

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Available from: Shubham Vyas, Feb 17, 2014
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    • "The CHelpG charge analysis shows that the larger negative charge resides on the oxygen atom of Ortho-7 (−0.5063) compared to 2-PAM (−0.4371) (Table 1). This charge analysis indicates that Ortho-7 will be a better nucleophile compared to 2-PAM [48]. The Wiberg bond index calculated for the P…O(Ortho-7) bond of C1b is found to be 0.008 au, which is higher than that of P…O(2-PAM) bond (0.005 au) for C1a, implying a stronger interaction in the reactant complex of Ortho-7 compared to 2-PAM [45], [46]. "
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