β-Aminoalcohols as Potential Reactivators of Aged Sarin-/Soman-Inhibited Acetylcholinesterase
β-Aminoalcohols as Potential Reactivators of Aged Sarin-/Soman-Inhibited Acetylcholinesterase
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β-氨基醇作为老化沙林/索曼抑制的乙酰胆碱酯酶的潜在再激活剂
DOI：
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
A. Wallqvist
中科院分区：
文献类型：
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作者：
I. Khavrutskii;A. Wallqvist
有机磷神经毒剂通过与其催化丝氨酸残基形成共价加合物来抑制参与神经信号转导的乙酰胆碱酯酶（AChE）。与索曼和沙林神经毒剂的乙酰胆碱加合物分别在几分钟和几小时内经历脱烷基化，这一过程被称为老化。这种转化是有害的，因为它阻止了乙酰胆碱酯酶与已知的肟基解毒剂的再激活。在这里，我们设计了一个β-氨基醇分子，用于老化乙酰胆碱酯酶的再激活，使用多层计算方法。这种方法包括高质量的量子力学/分子力学计算，提供可靠的再激活步骤和能量学。计算表明，设计的β-氨基醇可以选择性地重新激活沙林/索曼抑制的老化乙酰胆碱酯酶。此外，与现有的解毒剂不同，设计的β-氨基醇缺乏永久电荷，这使得它在中枢神经系统中具有潜在的活性。这项研究的机制见解可以帮助指导开发新的乙酰胆碱酯再激活剂，改善进入中枢神经系统的途径。
Organophosphate nerve agents inhibit the enzyme acetylcholinesterase (AChE), which is involved in nerve signal transduction, by forming covalent adducts with its catalytic serine residue. AChE adducts with soman and sarin nerve agents undergo dealkylation, a process known as aging, within a few minutes and a few hours, respectively. This transformation is detrimental because it precludes reactivation of AChE with known oxime-based antidotes. Here, we designed a β-aminoalcohol molecule for aged AChE reactivation, using a multi-tiered computational approach. This approach includes high-quality quantum mechanical/molecular mechanical calculations, providing reliable reactivation steps and energetics. The calculations suggest that the designed β-aminoalcohol can selectively reactivate aged sarin-/soman-inhibited AChE. Furthermore, unlike existing antidotes, the designed β-aminoalcohol lacks a permanent charge, making it potentially active in the central nervous system. The mechanistic insights of this study can help guide the development of new AChE reactivators with improved access to the central nervous system.
DOI：
10.1021/jp307790v
发表时间：
2012-09
期刊：
The journal of physical chemistry. B
影响因子：
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作者：
Gulseher Sarah Sirin;Yanzi Zhou;Lee Lior-Hoffmann;Shenglong Wang;Yingkai Zhang
通讯作者：
Gulseher Sarah Sirin;Yanzi Zhou;Lee Lior-Hoffmann;Shenglong Wang;Yingkai Zhang