Analytical Science Discipline, Central Salt & Marine Chemicals Research Institute (Council of Scientific and Industrial Research), Bhavnagar, Gujarat 364 002, India.
J Mol Graph Model. 2011 Aug;29(8):1039-46. doi: 10.1016/j.jmgm.2011.04.009. Epub 2011 May 6.
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.
由于有机磷 (OP) 化合物的抑制作用，乙酰胆碱酯酶 (AChE) 的失活对人类构成了重大威胁，因为 AChE 是神经递质传递过程中的关键酶。肟类化合物由于其α-效应亲核反应性而被用作 OP 抑制的 AChE 的潜在重激活剂。在寻找更有效的重激活剂的过程中，模型研究表明，α-效应对于去膦酰化反应并不是那么重要。我们报告了亲核反应性的α-效应对于羟胺阴离子对 OP 抑制的 AChE 重激活的重要性。我们已经通过 DFT [B3LYP/6-311G(d,p)] 计算证明，与报道的其他亲核试剂相比，羟胺阴离子与沙林-丝氨酸加合物 2 的重激活过程更有效。在存在和不存在 Gly121 和 Gly122 的氢键相互作用的情况下，观察到羟胺阴离子与沙林-丝氨酸加合物 3 和 4 相比，对沙林抑制的 AChE 的重激活作用优于甲肟阴离子。计算结果表明，在不存在和存在这种氢键相互作用的情况下，与甲肟阴离子相比，加合物 4 与羟胺阴离子的重激活过程的速率分别快 261 和 223 倍。DFT 计算结果表明，Glu202 的相邻羰基对沙林-丝氨酸加合物，特别是与甲肟阴离子的重激活的重要性。与其他亲核试剂相比，发现羟胺阴离子和沙林-丝氨酸加合物之间的反向重激活反应的能量更高，这表明这种α-亲核试剂可以作为重激活过程的良好解毒剂。
