STRUCTURAL AND DYNAMIC ASPECTS OF DRUG/DNA INTERACTIONS

药物/DNA 相互作用的结构和动力学方面

• 批准号: 2838566
• 负责人: DAVID E WEMMER
• 金额: $ 15.76万
• 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 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2838566
• 关键词: DNA; antibiotics; chemical binding; chemical models; chemical substitution; conformation; dimer; drug /agent; imidazole; intermolecular interaction; ligands; nuclear magnetic resonance spectroscopy; nucleic acid sequence; nucleic acid structure; synthetic nucleic acid

DESCRIPTION: The goal of this project is to continue to improve understanding of ligands which interact with DNA in a sequence specific manner, and to improve the design of such molecules. Ligands designed to target any particular DNA sequence with both high affinity and specificity would be very useful in biochemistry and molecular biology, and also potentially as therapeutic agents. the investigator's focus has been derivatives of the natural product distamycin, containing three pyrrole rings, which has a preference for binding in the minor groove at sequences containing four sequential A,T pairs. He has demonstrated that synthetic derivatives containing imidazole rings bind selectively at specific sequences containing both A,T and G,C pairs, utilizing hydrogen bonding to recognize the amino group of guanosine in the minor groove. Different combinations of these 'recognition modules' have been demonstrated to bind specifically at a number of different DNA sequences, including mostly G,C pairs. Linking such modules has allowed recognition of sites up to 13 base pairs in long. Work proposed will extend studies of linked ligands for recognition of general, mixed A,T and G,C sequences. Linking different recognition modules for enhancing specificity in binding has been shown, and good linkers have been found. For some binding modes the linkers affect the binding affinity and specificity. Dr. Wemmer will study several linked ligand complexes by NMR to understand the interactions with DNA, which will allow development of optimal designs. Linkers for hairpin complexes and extended complexes, with the linker partially controlling the preferred binding mode, and inflexible extensions will be examined. A particularly important area in the next period will be to better understand the factors which control specificity in binding of these designed ligands. The ligands which have been designed do in fact bind with significant preference for the selected target sites. However, there is a substantial range of discrimination between correct and incorrect or mismatched sites. The problem of discrimination seems to increase as the number of G:C pairs in the target site increases. Dr. Wemmer has two challenges, first to understand the origin of these effects, and second to control them. Meeting these challenges will also require developing new methods for determining the specificity for ligands which recognize long target sequences. A final area of work will be to link the minor groove binding agents to other molecules which can be used for sensitive detection, or to carry out chemistry on the target DNA.

描述：该项目的目标是持续改进 了解以特定序列与 DNA 相互作用的配体 方式，并改进此类分子的设计。 配体设计用于 以高亲和力和特异性靶向任何特定 DNA 序列 在生物化学和分子生物学中非常有用，而且 可能作为治疗剂。 调查员的重点是 天然产物偏端霉素的衍生物，含有三个吡咯 环，它优先结合在序列的小凹槽中 包含四个连续的 A、T 对。 他证明了合成 含有咪唑环的衍生物在特定位置选择性结合 包含 A,T 和 G,C 对的序列，利用氢键 识别小沟中鸟苷的氨基。 不同的 这些“识别模块”的组合已被证明可以结合 特别针对许多不同的 DNA 序列，主要包括 G、C 对。 连接这些模块可以识别多达 13 个碱基的位点 对长。 拟议的工作将扩展连接配体的研究，以识别 一般，混合 A、T 和 G、C 序列。 连接不同的识别模块 已显示出增强结合特异性的作用，并且良好的接头已被证明 被发现了。 对于某些结合模式，接头会影响结合亲和力 和特异性。 Wemmer 博士将通过以下方法研究几种连接的配体复合物 NMR 用于了解与 DNA 的相互作用，这将有助于开发 最佳设计。 发夹复合物和延伸复合物的接头，具有 链接器部分控制首选绑定模式，并且不灵活 将检查扩展。 下一个时期一个特别重要的领域将是更好地 了解控制这些结合特异性的因素 设计的配体。 所设计的配体实际上确实与 对选定的目标站点具有显着偏好。 然而，有一个 正确与错误之间存在很大范围的区分，或者 不匹配的网站。 歧视问题似乎随着 目标位点中 G:C 对的数量增加。 Wemmer 博士有两个 挑战，首先要了解这些影响的根源，其次要 控制他们。 应对这些挑战还需要开发新的 确定识别长配体的特异性的方法 目标序列。 最后一个工作领域是将小沟结合剂连接到 其他可用于灵敏检测或进行 目标 DNA 上的化学反应。