In Silico Pharmacophore Model for Tabun-Inhibited Acetylcholinesterase Reactivators: A Study of Their Stereoelectronic Properties
In Silico Pharmacophore Model for Tabun-Inhibited Acetylcholinesterase Reactivators: A Study of Their Stereoelectronic Properties
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DOI：
10.1021/tx900192u
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发表时间：
2010-01-01
影响因子：
4.1
通讯作者：
Gordon, Richard K.
中科院分区：
文献类型：
--
作者：
Bhattacharjee, Apurba K.;Kuca, Kamil;Gordon, Richard K.
抑制神经系统中乙酰胆碱酯酶（AChE; EC 3.1.1.7）功能的有机磷（OP）神经毒剂，可引起急性中毒。如果不治疗，可能导致死亡。被抑制的乙酰胆碱酯酶可被肟类药物重新激活，肟类药物是OP暴露的解毒剂。然而，OP中毒引起的神经毒剂塔崩（GA）是特别耐肟，这很难重新激活GA抑制乙酰胆碱酯酶。为了尝试开发一种合理的策略，用于发现和设计具有较低毒性和提高重新激活GA抑制的ACME功效的新型重新激活剂，我们从一组11个肟中开发了第一个用于GA抑制的AChE结合亲和力的计算机模拟药效团模型。肟的立体电子分布和三维定量构效关系的药效团使用从头算量子化学和药效团生成方法进行了分析。从半经验AM 1层次从头计算的量子化学方法顺序使用，以确定9个肟表现出的亲和力结合GA抑制的乙酰胆碱酯酶在体内的立体电子性质。计算的立体电子性质导致我们使用CATALYST方法开发了计算机药效团模型。具体的立体电子配置文件，包括在肟，亲水性，表面积，亲核性的肟氧的吡啶环的双季氮原子之间的距离，和位置的分子轨道上的isosurfaces具有重要的作用，为重新激活GA抑制乙酰胆碱酯酶的效力。肟与GA抑制的AChE结合的电子药效团模型需要一个氢键受体，在两个末端区域需要一个氢键供体，在肟的中心区域需要一个芳环。该模型被认为是良好的相关性（R = 0.9）与实验肟亲和力结合GA抑制AChE。额外的sterecelectronic功能相关的活动与位置的分子轨道和弱静电势场的芳香环，被认为是一致的药效团模型。这些结果提供了第一个预测药效团模型的肟亲和力结合对GA抑制AChE。该模型可用于化合物文库的虚拟筛选以发现和/或定制合成可用于GA中毒的更有效且毒性更小的再活化剂。
Organophosphorus (OP) nerve agents that inhibit acetylcholinesterase (AChE; EC 3.1.1.7) function in the nervous system, causing acute intoxication. If Untreated, death can result. Inhibited AChE call be reactivated by oximes, antidotes for OP exposure. However, OP intoxication caused by the nerve agent tabun (GA) is particularly resistant to oximes, which poorly reactivate GA-inhibited AChE. In an attempt to develop a rational strategy for the discovery and design of novel reactivators with lower toxicity and increased efficacy in reactivating GA-inhibited ACME, we developed the first in silico pharmacophore model for binding affinity of GA-inhibited AChE from a set of 11 oximes. Oximes were analyzed for stereoelectronic profiles and three-dimensional quantitative structure-activity relationship pharmacophores using ab initio quantum chemical and pharmacophore generation methods. Quantum chemical methods were sequentially used from semiempirical AM1 to hierarchical ab initio Calculations to determine the stereoelectronic properties of nine oximes exhibiting affinity for binding to GA-inhibited AChE in vivo. The Calculated stereoelectronic properties led US to develop the in silico pharmacophore model using CATALYST methodology. Specific stereoelectronic profiles including the distance between bisquarternary nitrogen atoms of the pyridinium ring in the oximes, hydrophilicity, surface area, nucleophilicity of the oxime oxygen, and location of the molecular orbitals on the isosurfaces have important roles for potencies for reactivating GA-inhibited AChE. The in silico pharmacophore model of oxime affinity for binding to GA-inhibited AChE was found to require a hydrogen bond acceptor, a hydrogen bond donor at the two terminal regions, and in aromatic ring in the central region of the oximes. The model was found to be well-correlated (R = 0.9) With experimental oxime affinity for binding to GA-inhibited AChE. Additional sterectelectronic features relating activity with the location of molecular orbitals and weak electrostatic potential field over the aromatic rings were, found to be consistent with the pharmacophore model. These results provided the first predictive pharmacophore model of oxime affinity for binding toward GA-inhibited AChE. The model may be Useful for virtual screening of compound libraries to discover and/or custom synthesize more efficacious and less toxic reactivators that may be useful for GA intoxication.