STRUCTURAL AND DYNAMIC ASPECTS OF DRUG-DNA RECOGNITION

药物 DNA 识别的结构和动态方面

• 批准号: 3302074
• 负责人: DAVID E WEMMER
• 金额: $ 8.37万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3302074
• 关键词: DNA; antibiotics; chemical binding; chemical structure; conformation; drug /agent; high performance liquid chromatography; nucleic acid sequence; nucleic acid structure; nucleobase; synthetic nucleic acid

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.

该项目的目标是提高我们对药物的了解 结合在 DNA 小沟中，优先选择特定序列。 准备的种类相当多，几乎 所有这些都更喜欢结合在富含 A-T 的 DNA 区域。 目前 这种序列偏好的基础尚不清楚，阻碍了 进一步设计具有改进的结合特异性的新分子。 这 即将完成的工作将主要使用核磁共振波谱来识别 DNA寡聚物上有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，以及肌苷-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了解具体的 需要确定的功能组，并将 研究，这应该有助于理解结构特征 导致优先绑定。 利用这一点的可能性 探索新药的协同结合模式。 其机制 药物分子在可用结合位点之间的转移也将 被确定。 核磁共振波谱提供了一种同时进行 确定许多不同的传输速率。 结构的改变 将使用已知药物来确定对结合位点的影响 特异性和交换动力学。