A thermodynamic signature for drug-DNA binding mode
A thermodynamic signature for drug-DNA binding mode
复制标题
DOI：
10.1016/j.abb.2006.03.027
复制
发表时间：
2006-09-01
影响因子：
3.9
通讯作者：
Chaires, Jonathan B.
中科院分区：
文献类型：
--
作者：
Chaires, Jonathan B.
许多小分子直接和选择性地与DNA结合，通过抑制复制、转录或拓扑异构酶活性而起到化疗药物的作用。这些小分子的两种常见的结合模式是插层结合或沟槽结合。插入的结果是在DNA碱基对之间插入一个平面芳香取代基，伴随而来的是DNA螺旋的解离和延长。相反，沟槽结合不会在任何程度上扰乱双链结构。凹槽粘结剂通常是新月形的，贴合在小凹槽中，DNA结构几乎没有扭曲。最近的量热研究已经确定了具有代表性的DNA结合化合物的焓和熵对DNA结合的贡献。对这些从文献中挑选出来的热力学数据的分析揭示了沟槽键合化合物和插层化合物的独特的热力学特征。26种药物DNA相互作用的结合能(H)与结合熵(-T，S)的关系图表明，沟槽结合作用聚集在自由能具有有利熵贡献的区域，而嵌入体聚集在具有不利熵贡献但具有有利焓贡献的区域。凹槽结合主要是以熵驱动的，而插层是以焓驱动的。这两种结合模式的热力学特征对比的分子基础还不清楚，但这种模式应该可以用于对新的DNA结合剂进行分类。(C)2006 Elsevier Inc.保留所有权利。
A number of small molecules bind directly and selectively to DNA, acting as chemotherapeutic agents by inhibiting replication, transcription or topoisomerase activity. Two common binding modes for these small molecules are intercalation or groove-binding. Intercalation results from insertion of a planar aromatic substituent between DNA base pairs, with concomitant unwinding and lengthening of the DNA helix. Groove binding, in contrast, does not perturb the duplex structure to any great extent. Groove-binders are typically crescent-shaped, and fit snugly into the minor groove with little distortion of the DNA structure. Recent calorimetric studies have determined the enthalpic and entropic contributions to the DNA binding of representative DNA binding compounds. Analysis of such thermodynamic data culled from the literature reveals distinctive thermodynamic signatures for groove-binding and intercalating compounds. Plots of the binding enthalpy (Delta H) against binding entropy (-T Delta S) for 26 drug DNA interactions reveal that groove-binding interactions are clustered in a region of the graph with favorable entropy contributions to the free energy, while intercalators are clustered in a region with unfavorable entropy but favorable enthalpy contributions. Groove-binding is predominantly entropically driven, while intercalation is enthalpically driven. The molecular basis of the contrasting thermodynamic signatures for the two binding modes is by no means clear, but the pattern should be of use in categorizing new DNA binding agents. (c) 2006 Elsevier Inc. All rights reserved.