DRUG-DNA INTERACTIONS--A THERMODYNAMIC STUDY

我们的长期目标是发展对分子力的理解 决定和控制药物结合的亲和力和特异性， DNA. 这种对药物-DNA相互作用的分子理解是一种 为药物设计的合理性奠定基础。 我们 方法是确定完整的热力学结合概况的 几种抗肿瘤和抗病毒药物与不同DNA宿主络合作用 双链体。 具体来说，光谱学和批量量热法将是 用于在化学上表征结合事件作为函数 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特征 将允许我们：定义驱动复杂化的力量的性质 并预测复合物的温度依赖性稳定性;确定 序列结合偏好的热力学起源;定义 协同结合的热力学基础;评估特异性结合的作用 通过比较一系列结合数据来确定药物的结构特征 药物类似物;将热力学数据与 结合和复合物的分子图像;解决药物诱导的 局部特异性药物-DNA相互作用引起的构象变化， 比较相应的寡聚和多聚DNA宿主上的结合数据; 通过比较结合来评估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。 微分 扫描量热法将用于检测，监测，并 表征药物结合对聚合物的熔融行为的影响。 主机双工。 特别地，用于熔化的协同熔化单元的尺寸可以是合适的。 每个宿主双链体将在存在和不存在每个 药 该参数将提供药物影响的量度。 结合和碱基序列对聚合物链增长能力的影响 分子扭曲--一种毫无疑问是 在许多生物过程中的重要性。 量热法代表了 唯一的实验方法，相关的热力学数据可以 以直接和独立于模型的方式获得。 结合 标准的光谱技术，该建议旨在利用 独特的批量和差示扫描量热法的权力，以获得 溶液的完整热力学和超热力学分布 药物结合的性质和所得的药物-DNA复合物。

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.