DRUG-DNA INTERACTIONS--A THERMODYNAMIC STUDY

我们的长期目标是发展对分子力的理解 规定和控制药物结合到的亲和力和特异性 DNA这种对药物-DNA相互作用的分子理解是一种 制定合理的药物设计的前提条件。我们的 方法是确定完整的热力学结合轮廓 几种抗肿瘤和抗病毒药物与不同DNA宿主的络合作用 双面的。具体地说，光谱学和间歇量热法将 被用来将结合事件热力学地表征为函数 该药物的结构和寡聚体和 聚合宿主DNA。每种药物的热力学结合谱 将使我们能够：定义推动复杂性的力量的性质 并预测了络合物的温度稳定性；确定了 序列结合首选项的热力学起源；定义 协同结合的热力学基础；评价特定的作用 通过比较一系列结合数据来确定药物的结构特征 将热力学数据与药物类似物的模型进行关联 结合和络合物的分子图像；解决药物诱导的 局部、特定药物与DNA相互作用的构象变化 比较对应的寡聚和聚合DNA主机上的结合数据； 通过比较结合评价药物协同作用的热力学基础 在存在和不存在其他药物的情况下的药物数据。差动 扫描量热法将用于检测、监测和热力学 表征药物结合对熔融行为的影响 主机双工。特别是，合作熔化单元的大小 每个主机双工将根据每个主机是否存在而确定 毒品。此参数将提供药物影响的度量 基于高聚物链的繁殖能力的结合和碱基序列 分子扭曲--这一特性无疑具有重大意义 在许多生物过程中具有重要意义。量热法代表了 只有实验方法才能得到相关的热力学数据 以直接和独立于模型的方式获得。与 标准光谱技术，这项提议旨在利用 独特的批量和差示扫描量热仪功能，可获得 溶液的完整热力学和热力学外轮廓 药物结合的性质和生成的药物-DNA络合物。

Our long-term goal is to develop an understanding of the molecular forces that dictate and control the affinity and specificity of drug binding to DNA. Such a molecular understanding of drug-DNA interactions is a prerequisite for the development of a rational basis for drug design. Our approach is to determine complete thermodynamic binding profiles for the complexation of several antitumor and antiviral drugs to various DNA host duplexes. Specifically, spectroscopy and batch calorimetry will be employed to characterize thermodynamically the binding event as a function of the structure of the drug and the sequence of both oligomeric and polymeric host DNA's. These thermodynamic binding profiles for each drug will allow us to: define the nature of the forces that drive complexation and predict the temperature-dependent stability of the complex; determine the thermodynamic origin of sequence binding preferences; define the thermodynamic basis for cooperative binding; evaluate the role of specific structural features of the drug by comparing the binding data on a series of drug analogues; correlate the thermodynamic data with the mode of binding and the molecular picture of the complex; resolve drug-induced conformational changes from local, specific drug-DNA interactions by comparing binding data on corresponding oligomeric and polymeric DNA hosts; evaluate the thermodynamic basis for drug synergism by comparing binding data for a drug in the presence and absence of other drugs. Differential scanning calorimetry will be used to detect, monitor, and thermodynamically characterize the influence of drug binding on the melting behavior of the host duplex. In particular, the size of the cooperative melting unit for each host duplex will be determined in the presence and absence of each drug. This parameter will provide a measure of the influence of drug binding and base sequence on the ability of a polymer chain to propagate molecular distortions -- a property which undoubtedly is of great importance in numerous biological processes. Calorimetry represents the only experimental method by which the relevant thermodynamic data can be obtained in a direct and model-independent manner. In conjunction with standard spectroscopic techniques, this proposal is designed to exploit the unique powers of batch and differential scanning calorimetry to obtain complete thermodynamic and extra-thermodynamic profiles of the solution properties of drug binding and the resultant drug-DNA complexes.