Nucleophilic Reactivation of Sarin-Inhibited Acetylcholinesterase: A Molecular Modeling Study

被引:32
|
作者
Delfino, Reinaldo T. [1 ]
Figueroa-Villar, Jose D. [1 ]
机构
[1] Inst Mil Engn, Secao Engn Quim, BR-22290070 Rio De Janeiro, Brazil
来源
JOURNAL OF PHYSICAL CHEMISTRY B | 2009年 / 113卷 / 24期
关键词
POLARIZABLE CONTINUUM MODEL; ACTIVE-SITE GORGE; AB-INITIO; PHOSPHONYLATION MECHANISMS; TORPEDO-CALIFORNICA; CHARGE-DISTRIBUTION; CATALYTIC POWER; RESIDUES; ORGANOPHOSPHORUS; HYDROLYSIS;
D O I
10.1021/jp810686k
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Oximes have been used as reactivators for organophosphorus-inhibited acetylcholinesterase (AChE). However, it is still not clear why oximes are more efficient than other nucleophiles, since the reactivation consists of a simple nucleophilic substitution. In an attempt to answer this question, we have modeled the sarin-inhibited AChE reactivation by other nucleophiles (with and without the so-called alpha-effect) by applying the B3LYP/6-311G(d,p) level of theory. We have concluded that oximes reactivate AChE by a three-step mechanism in opposition to the four-step processes of the other modeled nucleophiles. In addition, our model suggests that oximes react with AChE in the deprotonated form (oximate). Our results also indicate that other nucleophiles may be used as AChE reactivators. We propose the use of hydrazones and hydrazonates for further evaluation as antidotes for intoxication by chemical warfare agents.
引用
收藏
页码:8402 / 8411
页数:10
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