Voronoi binding site models
Voronoi binding site models
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Voronoi 结合位点模型
DOI：
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发表时间：
1987
期刊：
影响因子：
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通讯作者：
G. Crippen
中科院分区：
文献类型：
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作者：
G. Crippen
在药物设计和酶学中经常出现的一个问题是，几种化合物与同一位点的结合常数是已知的，但该位点的几何形状和能量相互作用是未知的。本文详细介绍了一种精确而紧凑地表示每个配体的允许构象空间的新方法，准确地描述了它们的三维结构，并实际地使每个配体在能量上最有利的位置上采用构象和定位。研究者只提供配体结构和观察到的结合自由能，以及提出的位置几何形状。在没有进一步假设配体如何结合以及配体的哪些部分对确定结合很重要的情况下，该算法拟合观察到的结合能而不留下异常值，准确地预测每个给定配体在位点上的结合方式，并预测新化合物的结合强度和模式，而不考虑与原始配体的化学相似性。该方法通过设计一个简单的位点来说明5个多氯联苯与甲状腺素结合前白蛋白的结合。然后，该模型正确地预测了另外六个联苯的结合能，但在一个化合物上失败了。
A frequently occurring problem in drug design and enzymology is that the binding constants for several compounds to the same site are known, but the geometry and energetic interactions of the site are not. This paper presents in detail a novel approach to the problem which accurately but compactly represents the allowed conformation space of each ligand, accurately depicts their three‐dimensional structures, and realistically allows each ligand to adopt the conformation and positioning in the site which is most favorable energetically. The investigator supplies only the ligand structures and observed binding free energies, along with a proposed site geometry. With no further assumptions about how the ligands bind and what parts of the ligands are important in determining the binding, the algorithm fits the observed binding energies without leaving outliers, predicts exactly how each of the given ligands binds in the site, and predicts the strength and mode of binding of new compounds, regardless of chemical similarity to the original set of ligands. The method is illustrated by devising a simple site that accounts for the binding of five polychlorinated biphenyls to thyroxine binding prealbumin. This model then predicts the binding energies correctly for an additional six biphenyls, and fails on one compound.
物理化学参数在距离几何和相关三维定量构效关系中的应用：使用大肠杆菌二氢叶酸还原酶抑制剂的演示。
影响因子：
7.3
作者：
Ghose,AK;Crippen,GM
通讯作者：
Crippen,GM