Specificity of Intercalation Reactions

描述（由申请人提供）：DNA是小分子治疗剂未被充分代表的靶标。缺乏DNA靶向药物的一个原因是，控制序列和结构选择性配体与DNA结合的基本分子机制尚不清楚。合理设计新的DNA靶向药物需要对现有化合物的结合机制有透彻的了解，这些化合物与DNA的结合具有独特的特异性类型。该研究的长期目标是了解插层反应的分子机制，重点是插层反应序列和结构选择性结合的能量基础。更新是寻求一个成功的和高产的基础科学计划，已经产生了几个有希望的途径dna靶向药物的开发。下一个资助期的研究将侧重于旨在阐明控制结构和序列选择性配体与核酸结合的机制的创新研究。具体目标包括：1。使用和改进高通量竞争透析测定，用于鉴定和表征与核酸结合的结构选择性配体。2. 配体与DNA结合的表征：RNA杂化结构。3. 用一种新的量热“引导印刷”方法表征区域选择性药物结合。这些研究的结果将：1。提供与核酸结合的结构选择性配体的明确分类，以及该结构选择性的能量基础的描述。为指导合理设计靶向DNA:RNA杂交结构的化合物提供基础信息，这是一种具有巨大生物学意义的靶标。3. 为长（基因组）DNA片段中药物-DNA相互作用的定量研究提供了新的工具。

DESCRIPTION (provided by applicant): DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA-targeted drugs is that the fundamental molecular mechanisms that govern sequence and structural-selective ligand binding to DNA are poorly understood. The rational design of new DNA-targeted drugs requires a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of specificity. The long-range goal of the proposed research is to understand the molecular mechanism of intercalation reactions, with emphasis on the energetic basis of their sequence and structural selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Research in the next funding period will focus on innovative studies designed to clarify the mechanisms that govern structural and sequence selective ligand binding to nucleic acids. Specific aims include: 1. Use and refinement of a highthroughput competition dialysis assay for the identification and characterization of structural selective ligand binding to nucleic acids. 2. Characterization of ligand binding to DNA:RNA hybrid structures. 3. Characterization of regional-selective drug binding by a novel calorimetric "bootprinting" method. The results of these studies will: 1. Provide a definitive taxonomy of structural selective ligand binding to nucleic acids, along with a description of the energetic basis of that structural selectivity, 2. Provide fundamental information to guide the rational design of compounds targeted to DNA:RNA hybrid structures, a target of enormous biological significance. 3. Provide a new tool for the quantitative study of drug-DNA interaction in long (genomic) pieces of DNA.