A role for water molecules in DNA-ligand minor groove recognition.
A role for water molecules in DNA-ligand minor groove recognition.
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DOI：
10.1021/ar800016q
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发表时间：
2009-01-20
影响因子：
18.3
通讯作者：
Wilson, W. David
中科院分区：
文献类型：
--
作者：
Nguyen, Binh;Neidle, Stephen;Wilson, W. David
通过与小分子结合来靶向DNA的小沟一直被认为是生物学中重要的分子识别策略。多种合成的杂环分子在双螺旋的小沟中非共价结合，并且也有效地对抗许多人类和动物疾病。一个经典的结构概念，即等螺旋原理，指导了这项工作的大部分：这样的杂环分子需要一个形状，以补充小沟的凸面。研究人员利用这一原理设计出了能够读取DNA序列的分子。这一原理还预测，缺乏互补形状要求的分子只会与DNA弱结合。然而，最近，研究人员意外地发现，一些基本上线性的化合物，不具有这种特征，可以具有高的DNA亲和力。在这个帐户中，我们讨论了一个替代的识别概念的基础上，这些新的发现。我们证明，高度结构化的水分子可以在配体和DNA小沟之间的介导中发挥关键作用，而不损失结合亲和力。结合结构和热力学的方法来理解这些分子的行为已经表明，在它们的DNA复合物中有不同类别的结合水。例如，将这种水桥概念应用于苯脒平台，发现了具有高水平生物活性和低非特异性毒性的分子。其中一些分子目前正在进行高级临床试验。
Targeting the minor groove of DNA through binding to a small molecule has long been considered an important molecular-recognition strategy in biology. A wide range of synthetic heterocyclic molecules bind non-covalently in the minor groove of the double helix and are also effective against a number of human and animal diseases. A classic structural concept, the isohelicity principle, has guided much of this work: such heterocyclic molecules require a shape that complements the convex surface of the minor groove. Researchers have used this principle to design molecules that can read DNA sequences. This principle also predicts that molecules that lack the complementary shape requirement would only bind weakly to DNA. Recently, however, researchers have unexpectedly found that some essentially linear compounds, which do not have this feature, can have high DNA affinity. In this Account, we discuss an alternative recognition concept based on these new findings. We demonstrate that highly structured water molecules can play a key role in mediating between the ligand and DNA minor groove without loss of binding affinity. Combined structural and thermodynamic approaches to understanding the behavior of these molecules have shown that there are different categories of bound water in their DNA complexes. For example, application of this water-bridging concept to the phenylamidine platform has resulted in the discovery of molecules with high levels of biological activity and low non-specific toxicity. Some of these molecules are now in advanced clinical trials.
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影响因子：
3.8
作者：
Liu, Yang;Kumar, Arvind;Wilson, W. David
通讯作者：
Wilson, W. David
影响因子：
3.9
作者：
Midgley, Ian;Fitzpatrick, Karen;Trendler, Kerri L.
通讯作者：
Trendler, Kerri L.
影响因子：
7.3
作者：
GOODSELL, D;DICKERSON, RE
通讯作者：
DICKERSON, RE
DOI：
10.1080/07391102.1989.10508505
发表时间：
1989-12-01
影响因子：
4.4
作者：
LARSEN, TA;GOODSELL, DS;DICKERSON, RE
通讯作者：
DICKERSON, RE
影响因子：
2.9
作者：
GOODSELL, DS;KOPKA, ML;DICKERSON, RE
通讯作者：
DICKERSON, RE