DRUG-DNA INTERACTIONS--THERMODYNAMICS OF REOGNITION

我们的长期目标是描述宇宙的热力学性质 决定和控制分子亲和力和特异性的分子作用力 药物与DNA结构的结合。药物-DNA的这样一个特征 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整的热力学束缚 抗肿瘤和抗病毒药物的络合作用及其研究概况 类似于各种DNA主机双链。具体地说，光谱和 量热技术将被用来表征热力学 结合事件作为药物的结构和 寡聚体和聚合体宿主DNA的序列。结果 热力学结合曲线将使我们能够：定义 驱动络合的作用力并预测与温度有关的 络合物的稳定性；确定序列的热力学起源(S) 约束偏好；定义合作的热力学基础 绑定；评估特定结构特征对 比较药物对DNA结合亲和力和特异性的影响 一系列药物类似物的热力学结合数据；关联 结合模式的热力学数据和分子图 络合物；定义手性选择性的热力学基础；分解 药物诱导的局部、特异性药物DNA构象变化 通过比较相应齐聚物上的结合数据和 聚合DNA宿主；评估药物的热力学基础 协同作用(如联合化疗方案中发生的)通过比较 一种药物在存在和不存在其他药物的情况下的DNA结合数据。 差示扫描量热仪将用于检测、监控和 药物结合对熔融影响的热力学表征 主机双工的行为。尤其是合作社的规模 每个主机双工的熔化单位将在以下情况下确定 每种药物都不存在。此参数将提供 药物结合和碱基序列对聚合物性能的影响 传播熔化协同性所需的分子扭曲的链 --这一财产在许多地方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 通过它可以直接和直观地获得相关的热力学数据 独立于模型的方式。与标准光谱相结合 技术，这项提议旨在利用 等温混合和差示扫描量热法获得完全 溶液性质的热力学和超热力学分布 药物结合和生成的药物-DNA复合体。最重要的是， 结合结构数据，我们的热力学结合数据 具有系统结构改变的药物家族将使我们能够 定义特定药物与脱氧核糖核酸相互作用对 每个配体所表现出的DNA结合亲和力和特异性。AS 如上所述，这种对热力学的剖析和表征 特定药物-DNA相互作用的贡献代表了一个重要的 为药物开发合理的基础所需的漫长旅程中的一步 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.