title: Assessing the reactivation efficacy of hydroxylamine anion towards VX-inhibited AChE: a computational study.
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.
authors.affiliation: Analytical Science Discipline, Central Salt & Marine Chemicals Research Institute (Council of Scientific and Industrial Research), Bhavnagar, Gujarat, India.
authors.forename: Md Abdul Shafeeuulla
authors.initials: MA
authors.lastname: Khan
authors.forename: Bishwajit
authors.initials: B
authors.lastname: Ganguly
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000838:Anions; D000931:Antidotes / Q000737:chemistry*; D002619:Chemical Warfare Agents / Q000737:chemistry* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000737:chemistry*; D006801:Humans; D019811:Hydroxylamine / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D009946:Organothiophosphorus Compounds / Q000737:chemistry* / Q000633:toxicity; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D000110:Acetylcholinesterase; D000838:Anions; D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D019811:Hydroxylamine; D009946:Organothiophosphorus Compounds; C009680:VX-agent