STRUCTURAL AND DYNAMIC ASPECTS OF DRUG/DNA INTERACTIONS

描述：该项目的目标是继续改进 对特定序列中与DNA相互作用的配体的理解 并改进这种分子的设计。配基设计用于 靶向任何特定的DNA序列，具有高亲和力和特异性 将在生物化学和分子生物学中非常有用，而且 有可能被用作治疗剂。调查员的工作重点一直是 天然产物地塞霉素的衍生物，含有三个吡咯 环，其优先结合在序列的次槽中 包含四个顺序的A、T对。他已经证明了人工合成 含咪唑环的衍生物选择性地结合在特定的 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 这些“识别模块”的组合已经被证明可以结合 特别是一些不同的DNA序列，主要包括G，C 成对的。连接这样的模块允许识别多达13个碱基的位置 成对在长的。 拟议的工作将扩大对连接配体的研究，以识别 一般、混合的A、T和G、C序列。链接不同的识别模块 用于增强结合的特异性，并且良好的连接物具有 已经找到了。对于某些绑定模式，链接器会影响绑定亲和力 和专一性。Wemmer博士将通过以下方式研究几个连接的配体络合物 核磁共振以了解与DNA的相互作用，这将使开发 最优设计。发夹络合物和延伸络合物的连接物，带 该链接器部分地控制优选的绑定模式，并且不灵活 将对扩展进行检查。 下一阶段一个特别重要的领域将是更好地 了解控制这些结合的特异性的因素 设计了配基。已经设计好的配体实际上与 对选定的目标地点有很大的偏好。然而，有一个 在正确和不正确之间的很大范围的区分或 不匹配的站点。随着社会的发展，歧视问题似乎越来越严重 目标站点中G：C对的数量增加。Wemmer医生有两个 挑战，首先要了解这些影响的来源，其次是 控制他们。应对这些挑战还需要开发新的 确定识别Long的配基的特异性的方法 目标序列。 最后一项工作是将次要沟槽粘结剂连接到 其他可用于灵敏检测或进行 目标DNA上的化学反应。

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.