Oxime-induced reactivation of sarin-inhibited AChE: a theoretical mechanisms study.

Oximes (especially oximate anions) are used as potential reactivators of OP-inhibited AChE due to their unique alpha-effect nucleophilic reactivity. In the present study, by applying the DFT approach at the B3LYP/6-311G(d,p) level and the Møller-Plesset perturbation theory at the MP2/6-311G(d,p) level, the formoximate-induced reactivation patterns of the sarin-AChE adduct and the corresponding reaction mechanism have been investigated. The potential energy surface along the pathway of the reactivation reaction of sarin-inhibited AChE by oxime reveals that the reaction can occur quickly due to the relatively low energy barriers. A two-step process is a major pathway proposed for the studied reactivation reaction. Through the nucleophilic attack, the oximate first binds to the sarin-AChE adduct to form a relatively stable phosphorus complex. The regeneration of the serine takes place subsequently through an elimination step, which is expected to be competitive with the nucleophilic attacking process. The polarizable continuum model (PCM) has been applied to evaluate the solvate effects on the pathway. It is concluded that the reaction energy barriers are also low enough for the reaction to easily occur in solvent. The results derived from both the gas-phase model and the aqueous solvation model suggest that the studied oximate anion is an efficient antidote reagent for sarin-inhibited AChE.