DRUG-DNA INTERACTIONS--THERMODYNAMICS OF REOGNITION

我们的长期目标是表征的热力学性质的 决定和控制亲和性和特异性的分子力 药物与DNA结构的结合。 药物DNA的这种表征 互动是发展理性基础的先决条件， 药物设计 我们的方法是确定完全热力学结合 抗肿瘤和抗病毒药物的络合特性及其 与各种DNA宿主双链体类似。 具体而言，光谱和 将采用量热技术来表征 结合事件作为药物结构的函数， 寡聚体和聚合体宿主DNA的序列。 所得 热力学结合概况将使我们能够： 驱动络合并预测温度依赖性 复合物的稳定性;确定序列的热力学起源 结合偏好;确定合作的热力学基础 结合;评估特定结构特征的贡献， 通过比较药物与DNA结合的亲和力和特异性， 一系列药物类似物的热力学结合数据; 热力学数据与模式的结合和分子图片， 络合物;定义手性选择性的热力学基础;解析 局部特异性药物-DNA的药物诱导构象变化 通过比较相应的寡聚体和 聚合DNA宿主;评价药物的热力学基础 协同作用（如在联合化疗方案中发生的）， 在存在和不存在其他药物的情况下，药物的DNA结合数据。 差示扫描量热法将用于检测，监测， 表征药物结合对熔融的影响 主机双工器的行为。 特别是合作社的规模 每个宿主双链体的解链单位将在存在和 没有任何药物。 此参数将提供 药物结合和碱基序列对聚合物能力的影响 链来传播熔化协同性所需的分子扭曲 这一财产在许多国家可能具有相当重要的意义。 生物过程。 量热法是唯一的实验方法 通过该方法可以直接获得有关热力学数据， 独立模式。 结合标准光谱 技术，这项建议旨在利用独特的权力， 等温混合和差示扫描量热法，以获得完整的 溶液性质的热力学和超热力学分布 药物结合和由此产生的药物-DNA复合物。 最重要的是， 结合结构数据，我们的热力学结合数据 具有系统性改变结构的药物家族将使我们能够 定义特定药物与DNA相互作用对药物代谢的贡献 每种配体表现出的DNA结合亲和力和特异性。 作为 如上所述，这种热力学的解剖和表征 特定药物-DNA相互作用的贡献代表了一个重要的 在制定合理的药物基础所需的漫长旅程中迈出的一步 设计

Our long-term goal is to characterize the thermodynamic nature of the molecular forces that dictate and control the affinity and specificity of drug binding to DNA structures. Such a characterization 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 antitumor and antiviral drugs and their analogues to various DNA host duplexes. Specifically, spectroscopic and calorimetric techniques 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. The resulting thermodynamic binding profiles 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(s) of sequence binding preferences; define the thermodynamic basis for cooperative binding; evaluate the contribution that specific structural features of a drug make to its DNA binding affinity and specificity by comparing thermodynamic binding data for a series of drug analogues; correlate the thermodynamic data with the mode of binding and the molecular picture of the complex; define the thermodynamic basis for chiral selectivity; 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 the drug synergism (such as occurs in combined chemotherapy regiments) by comparing DNA 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 required for melting cooperativity -- a property which could be of considerable 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 isothermal mixing 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. Most significantly, in conjunction with structural data, our thermodynamic binding data on families of drugs with systematically altered structures will allow us to define the contribution(s) that specific drug-DNA interactions make to the DNA binding affinities and specificities exhibited by each ligand. As noted above, such a dissection and characterization of the thermodynamic contributions made by specific drug-DNA interactions represent an essential step in the long journey required to develop a rational basis for drug design.