Assessing the reactivation efficacy of hydroxylamine anion towards VX-inhibited AChE: a computational study

• Published in: Journal of molecular modeling 2012-05, Vol.18 (5), p.1801-1808
• Main Authors: Khan, Md Abdul Shafeeuulla, Ganguly, Bishwajit
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Anions; Antidotes - chemistry; Characterization and Evaluation of Materials; Chemical Warfare Agents - chemistry; Chemical Warfare Agents - toxicity; Chemistry; Chemistry and Materials Science; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - toxicity; Cholinesterase Reactivators - chemistry; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Humans; Hydroxylamine - chemistry; Kinetics; Models, Molecular; Molecular Medicine; Organothiophosphorus Compounds - chemistry; Organothiophosphorus Compounds - toxicity; Original Paper; Quantum Theory; Theoretical and Computational Chemistry; Thermodynamics
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-011-1209-y

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.