STRUCTURAL AND DYNAMIC ASPECTS OF DRUG-DNA RECOGNITION

这个项目的目标是提高我们对药物的理解 结合在DNA的小凹槽中，偏爱特定的序列。 有相当多的这些已经准备好了，几乎 所有这些都倾向于结合在DNA的A-T富集区。目前， 这种序列偏好的基础还没有被很好地理解，阻碍了 进一步设计具有改进的结合特异性的新分子。这个 将完成的工作将主要使用核磁共振光谱学来识别 多种药物在DNA寡聚体上的特异性结合位点。这些 将包括许多包含正常碱基对A-T的序列变体 和G-C，以及肌苷-胞嘧啶对，这不是自然发生的。 对绑定方式的比较将有助于我们理解特定的绑定方式 确定和将被识别的功能基团 调查，这应该有助于理解结构特征 导致优先约束。利用这一点的可能性 探索新药合作绑定模式。它的作用机制 药物分子在可用结合部位之间的转移也将 要下定决心。核磁共振光谱学提供了一种同时 确定许多不同的传输速率。结构上的改动 将对已知药物进行筛选，以确定其对结合部位的影响 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.