Assessing the Reactivation Efficacy of Hydroxylamine Anion Towards VX-inhibited AChE: a Computational Study

Overview

Journal J Mol Model

Publisher Springer

Specialty Molecular Biology

Date 2011 Aug 19

PMID 21850569

Authors

Md Abdul Shafeeuulla Khan

Bishwajit Ganguly

Affiliations

Soon will be listed here.

Abstract

Oximate anions are used as potential reactivating agents for OP-inhibited AChE because of they possess enhanced nucleophilic reactivity due to the α-effect. We have demonstrated the process of reactivating the VX-AChE adduct with formoximate and hydroxylamine anions by applying the DFT approach at the B3LYP/6-311 G(d,p) level of theory. The calculated results suggest that the hydroxylamine anion is more efficient than the formoximate anion at reactivating VX-inhibited AChE. The reaction of formoximate anion and the VX-AChE adduct is a three-step process, while the reaction of hydroxylamine anion with the VX-AChE adduct seems to be a two-step process. The rate-determining step in the process is the initial attack on the VX of the VX-AChE adduct by the nucleophile. The subsequent steps are exergonic in nature. The potential energy surface (PES) for the reaction of the VX-AChE adduct with hydroxylamine anion reveals that the reactivation process is facilitated by the lower free energy of activation (by a factor of 1.7 kcal mol(-1)) than that of the formoximate anion at the B3LYP/6-311 G(d,p) level of theory. The higher free energy of activation for the reverse reactivation reaction between hydroxylamine anion and the VX-serine adduct further suggests that the hydroxylamine anion is a very good antidote agent for the reactivation process. The activation barriers calculated in solvent using the polarizable continuum model (PCM) for the reactivation of the VX-AChE adduct with hydroxylamine anion were also found to be low. The calculated results suggest that V-series compounds can be more toxic than G-series compounds, which is in accord with earlier experimental observations.

References

Eddleston M, Szinicz L, Eyer P, Buckley N . Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. QJM. 2002; 95(5):275-83. PMC: 1475922. DOI: 10.1093/qjmed/95.5.275. View

Kirby A, Tondo D, Medeiros M, Souza B, Priebe J, Lima M . Efficient intramolecular general-acid catalysis of the reactions of alpha-effect nucleophiles and ammonia oxide with a phosphate triester. J Am Chem Soc. 2009; 131(5):2023-8. DOI: 10.1021/ja808746f. View

Kirby A, Davies J, Brandao T, da Silva P, Rocha W, Nome F . Hydroxylamine as an oxygen nucleophile. Structure and reactivity of ammonia oxide. J Am Chem Soc. 2006; 128(38):12374-5. DOI: 10.1021/ja065147q. View

Shafferman A, Kronman C, Flashner Y, Leitner M, Grosfeld H, Ordentlich A . Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding. J Biol Chem. 1992; 267(25):17640-8. View

Kolb H, Sharpless K . The growing impact of click chemistry on drug discovery. Drug Discov Today. 2003; 8(24):1128-37. DOI: 10.1016/s1359-6446(03)02933-7. View

Beck J, Hadad C . Hydrolysis of nerve agents by model nucleophiles: a computational study. Chem Biol Interact. 2008; 175(1-3):200-3. PMC: 2572228. DOI: 10.1016/j.cbi.2008.04.026. View

Delfino R, Figueroa-Villar J . Nucleophilic reactivation of sarin-inhibited acetylcholinesterase: a molecular modeling study. J Phys Chem B. 2009; 113(24):8402-11. DOI: 10.1021/jp810686k. View

Wang J, Gu J, Leszczynski J . Phosphonylation mechanisms of sarin and acetylcholinesterase: a model DFT study. J Phys Chem B. 2006; 110(14):7567-73. DOI: 10.1021/jp060370v. View

Wong L, Radic Z, Bruggemann R, Hosea N, Berman H, Taylor P . Mechanism of oxime reactivation of acetylcholinesterase analyzed by chirality and mutagenesis. Biochemistry. 2000; 39(19):5750-7. DOI: 10.1021/bi992906r. View

10.

Wang J, Gu J, Leszczynski J, Feliks M, Sokalski W . Oxime-induced reactivation of sarin-inhibited AChE: a theoretical mechanisms study. J Phys Chem B. 2007; 111(9):2404-8. DOI: 10.1021/jp067741s. View

11.

Wang J, Roszak S, Gu J, Leszczynski J . Comprehensive global energy minimum modeling of the sarin-serine adduct. J Phys Chem B. 2006; 109(2):1006-14. DOI: 10.1021/jp040574g. View

12.

Lee , Yang , PARR . Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B Condens Matter. 1988; 37(2):785-789. DOI: 10.1103/physrevb.37.785. View

13.

Khan M, Kesharwani M, Bandyopadhyay T, Ganguly B . Solvolysis of chemical warfare agent VX is more efficient with hydroxylamine anion: a computational study. J Mol Graph Model. 2009; 28(2):177-82. DOI: 10.1016/j.jmgm.2009.06.004. View

14.

Khan M, Lo R, Bandyopadhyay T, Ganguly B . Probing the reactivation process of sarin-inhibited acetylcholinesterase with α-nucleophiles: hydroxylamine anion is predicted to be a better antidote with DFT calculations. J Mol Graph Model. 2011; 29(8):1039-46. DOI: 10.1016/j.jmgm.2011.04.009. View

15.

Bandyopadhyay I, Kim M, Lee Y, Churchill D . Favorable pendant-amino metal chelation in VX nerve agent model systems. J Phys Chem A. 2006; 110(10):3655-61. DOI: 10.1021/jp055112x. View

16.

Maxwell D, Brecht K, Koplovitz I, Sweeney R . Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds?. Arch Toxicol. 2006; 80(11):756-60. DOI: 10.1007/s00204-006-0120-2. View

17.

Taylor P, Lappi S . Interaction of fluorescence probes with acetylcholinesterase. The site and specificity of propidium binding. Biochemistry. 1975; 14(9):1989-97. DOI: 10.1021/bi00680a029. View

18.

Seckute J, Menke J, Emnett R, Patterson E, Cramer C . Ab initio molecular orbital and density functional studies on the solvolysis of sarin and O,S-dimethyl methylphosphonothiolate, a VX-like compound. J Org Chem. 2005; 70(22):8649-60. DOI: 10.1021/jo0502706. View