Wang Jing, Gu Jiande, Leszczynski Jerzy, Feliks Mikolaj, Sokalski W Andrzej
Computational Center for Molecular Structure and Interactions, Department of Chemistry, Jackson State University, Jackson, Mississippi 39217, USA.
J Phys Chem B. 2007 Mar 8;111(9):2404-8. doi: 10.1021/jp067741s. Epub 2007 Feb 14.
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.
肟（尤其是肟酸根阴离子）因其独特的α-效应亲核反应性而被用作有机磷抑制的乙酰胆碱酯酶（AChE）的潜在重活化剂。在本研究中，通过在B3LYP/6-311G(d,p)水平应用密度泛函理论（DFT）方法以及在MP2/6-311G(d,p)水平应用莫勒-普莱斯特定则微扰理论，研究了甲肟诱导的沙林-AChE加合物的重活化模式及相应的反应机理。沿肟对沙林抑制的AChE进行重活化反应途径的势能面表明，由于能量壁垒相对较低，该反应能够快速发生。对于所研究的重活化反应，提出了一个两步过程作为主要途径。通过亲核攻击，肟酸根首先与沙林-AChE加合物结合形成相对稳定的磷配合物。随后丝氨酸通过消除步骤再生，预计该步骤与亲核攻击过程存在竞争。已应用极化连续介质模型（PCM）来评估溶剂化对该途径的影响。得出的结论是，反应能量壁垒也足够低，使得反应在溶剂中容易发生。气相模型和水溶剂化模型得出的结果均表明，所研究的肟酸根阴离子是沙林抑制的AChE的一种有效解毒试剂。
