Probing the reactivation process of sarin-inhibited acetylcholinesterase with α-nucleophiles: Hydroxylamine anion is predicted to be a better antidote with DFT calculations

Inactivation of acetylcholinesterase (AChE) due to inhibition by organophosphorus (OP) compounds is a major threat to human since AChE is a key enzyme in neurotransmission process. Oximes are used as potential reactivators of OP-inhibited AChE due to their α-effect nucleophilic reactivity. In search of more effective reactivating agents, model studies have shown that α-effect is not so important for dephosphylation reactions. We report the importance of α-effect of nucleophilic reactivity towards the reactivation of OP-inhibited AChE with hydroxylamine anion. We have demonstrated with DFT [B3LYP/6-311G(d,p)] calculations that the reactivation process of sarin–serine adduct 2 with hydroxylamine anion is more efficient than the other nucleophiles reported. The superiority of hydroxylamine anion to reactivate the sarin-inhibited AChE with sarin–serine adducts 3 and 4 compared to formoximate anion was observed in the presence and absence of hydrogen bonding interactions of Gly121 and Gly122. The calculated results show that the rates of reactivation process of adduct 4 with hydroxylamine anion are 261 and 223 times faster than the formoximate anion in the absence and presence of such hydrogen bonding interactions. The DFT calculated results shed light on the importance of the adjacent carbonyl group of Glu202 for the reactivation of sarin–serine adduct, in particular with formoximate anion. The reverse reactivation reaction between hydroxylamine anion and sarin–serine adduct was found to be higher in energy compared to the other nucleophiles, which suggests that this α-nucleophile can be a good antidote agent for the reactivation process.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (130 K)Download as PowerPoint slideHighlights► The remarkable efficacy of hydroxylamine anion towards the reactivation process of sarin-inhibited AChE adduct has been predicted with density functional calculations. ► The importance of neighbouring residues (Glu 202), oxyanion hole (Gly121, Gly122) and catalytic triad (His 447) has been explored. ► The influence of these residues is more pronounced in the reactivation process of sarin-inhibited AChE with formoximate anion compared to that of hydroxylamine anion. ► The DFT calculated results shed light on the importance of the adjacent carbonyl group of Glu202 for the reactivation process of sarin–serine adduct, in particular with formoximate anion.