STRUCTURAL AND DYNAMIC ASPECTS OF DRUG-DNA RECOGNITION

该项目的目标是提高我们对药物的理解， 结合在DNA的小沟中，优先选择特定的序列。 有相当多的各种各样的这些已经准备好了，几乎 所有这些都优选结合在DNA的富含A-T的区域。 目前 这种顺序偏好的基础还不清楚， 进一步设计具有改进的结合特异性的新分子。 的 将完成的工作将主要使用NMR光谱来识别 DNA寡聚体上多种药物的特异性结合位点。 这些 将包括许多含有正常碱基对A-T的序列变体 和G-C，还有肌苷-胞嘧啶对，它们不是天然存在的。 结合模式的比较将有助于我们理解特定的 需要确定的功能组， 调查，这应该有助于了解结构特征， 导致优先绑定。 利用这个机会 探索新药的协同结合模式。 的机制 药物分子在可用结合位点之间的转移也将 被确定。 NMR光谱提供了一种同时测定 确定多种不同的传输速率。 结构的改变 已知的药物将被用来确定对结合位点的影响 特异性和交换动力学。

The goal of this project is to improve our understanding of drugs which bind in the minor groove of DNA, with a preference for specific sequences. There are a considerable variety of these which have been prepared, almost all of which prefer binding at A-T rich regions of DNA. At present the basis for this sequence preference is not well understood, hampering further design of new molecules with improved binding specificity. The work which will be done will use primarily NMR spectroscopy to identify specific binding sites for a variety of drugs on DNA oligomers. These will include many sequence variants containing both normal base pairs, A-T and G-C, and also inosine-cytosine pairs, which do not occur naturally. The comparison of binding modes will help our understanding of specific functional groups which are required for identified and will be investigated, which should help in understanding structural features which lead to preferential binding. Possibilities of exploiting this cooperative binding mode in new drugs will be explored. The mechanisms of transfer of drug molecules between the available binding sites will also be determined. NMR spectroscopy provides a method for simultaneous determination of many different transfer rates. Alterations in structures of known drugs will be made to determine the effects on binding site specificity and exchange kinetics.