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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    ABSTRACT: We have examined the reactivation mechanism of the tabun-conjugated AChE with various drugs using density functional theory (DFT) and post-Hartree-Fock methods. The electronic environments and structural features of neutral oximes (deazapralidoxime and 3-hydroxy-2-pyridinealdoxime) and charged monopyridinium oxime (2-PAM) and bispyridinium oxime (Ortho-7) are different, hence their efficacy varies towards the reactivation process of tabun-conjugated AChE. The calculated potential energy surfaces suggest that a monopyridinium reactivator is less favorable for the reactivation of tabun-inhibited AChE compared to a bis-quaternary reactivator, which substantiates the experimental study. The rate determining barrier with neutral oximes was found to be ∼2.5 kcal/mol, which was ∼5.0 kcal/mol lower than charged oxime drugs such as Ortho-7. The structural analysis of the calculated geometries suggest that the charged oximes form strong O(…)H and N(…)H hydrogen bonding and C-H(…)π non-bonding interaction with the tabun-inhibited enzyme to stabilize the reactant complex compared to separated reactants, which influences the activation barrier. The ability of neutral drugs to cross the blood-brain barrier was also found to be superior to charged antidotes, which corroborates the available experimental observations. The calculated activation barriers support the superiority of neutral oximes for the activation of tabun-inhibited AChE compared to charged oximes. However, they lack effective interactions with their peripheral sites. Docking studies revealed that the poor binding affinity of simple neutral oxime drugs such as 3-hydroxy-2-pyridinealdoxime inside the active-site gorge of AChE was significantly augmented with the addition of neutral peripheral units compared to conventional charged peripheral sites. The newly designed oxime drug 2 appears to be an attractive candidate as efficient antidote to kinetically and structurally reactivate the tabun-inhibited enzyme.
    PLoS ONE 12/2013; 8(12):e79591. DOI:10.1371/journal.pone.0079591 · 3.23 Impact Factor
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    01/2011: pages 15-102; Издательство МГУ.
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    ABSTRACT: Pyrimidinium aldoximes are administered intravenously in cases of acute organophosphate poisoning. Since questions regarding their morphology and active conformation in the solution are still open, an effort was made to establish correspondence between their crystal state conformers and vibrational spectra, thus facilitating the future work on the assignment of bands in solution. Normal coordinate analysis including the potential energy distribution for all modes was performed for 1-methyl-pyridinium-2-aldoxime (PAM2AN) and 1-methyl-pyridinium-4-aldoxime (PAM4AN) cations (charge=+e, spin=0). Positions of infrared and Raman bands of corresponding chloride salts agree rather well with predicted values, except for modes taking part in hydrogen bonding to anions. The strength of hydrogen bonding is estimated to be of medium strength in both salts, the bonding in PAM2AN being stronger. The calculated and observed values of the characteristic stretching modes for the aldoxime moiety have been in accordance with the stronger acidity of PAM2AN structural isomer.
    Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy 05/2011; 78(5):1376-9. DOI:10.1016/j.saa.2011.01.012 · 2.35 Impact Factor
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