STRUCTURAL AND DYNAMIC ASPECTS OF DRUG-DNA INTERACTIONS

该项目的目标是提高我们对药物的理解， 结合在DNA的小格罗夫中，优先选择特定的序列。 我们将集中精力于偏端霉素-A，它结合到含有A：T的 四个或更多个碱基的序列，以及化学合成的 其，另外含有一个或多个G：C对结合序列 A：T。 这些化合物中序列偏好的基础不是 很好地理解，合理设计针对特定 序列很难。我们的结构特征将在 主要是利用核磁共振光谱，这使我们能够区分 溶液中不同的相互转化复合物，以确定结合 位点，并确定不同位点之间的转移动力学 结合位点。我们将对DNA序列进行系统的变异， 确定这类化合物对识别的影响。 新 将研究此类化学变体，特别是那些 含有取代天然偏端霉素吡咯的咪唑环， 以及具有四个或更多个连接环的那些。 我们还将继续 在制备可以2：1并排结合的二聚体药物方面的努力 模式 异源复合物（偏端霉素和lexitropsin结合在 相同位点），不仅获得碱基对类型 选择（G：C vs. A：T），而且还有方向选择（G：C vs. C：G）。 我们还将测量不同药物之间的药物交换率， 分子间和分子内的结合位点。 这些实验将 帮助我们理解离子对DNA识别的贡献， 分子配体。

The goal of this project is to improve our understanding of drugs which bind in the minor grove of DNA, with a preference for specific sequences. We will concentrate effort on distamycin-A, which binds to A:T containing sequences of four or more bases, and chemically synthesized analogs of it, that bind sequences which contain one or more G:C pairs in addition to A:Ts. The basis for the sequence preference in these compounds is not well understood, making rational design of analogs targeted to specific sequences difficult. our structural characterizations will be done primarily using NMR spectroscopy, which allows us to distinguish different interconverting complexes in solution, to identify the binding sites, and to determine the kinetics of transfer between different binding sites. we will carry out systematic variation of DNA sequences to determine the effects on recognition by this class of compounds. New chemical variants within this class will be studied, particularly those containing imidazole rings replacing pyroles of the natural distamycin, and those which have four or more linked rings. We will also continue efforts in preparing dimeric drugs which can bind in the side-by-side 2:1 mode. Use of hetero-complexes (a distamycin and a lexitropsin bound in the same site) will also be pursued to achieve not only base pair type selection (G:C vs. A:T), but also orientation selection (G:C vs. C:G). We will also measure the rate of exchange of drug between different binding sites, both inter- and intra-molecularly. Such experiments will help us understand ionic contributions to DNA recognition by small molecule ligands.