Specificity of Intercalation Reactions

超出提供的空间。对于小分子治疗剂来说，DNA是一个被低估的靶点。缺乏DNA靶向药物的一个原因是，人们对支配序列和结构选择性配体与DNA结合的基本分子机制知之甚少。新的DNA靶向药物的合理设计需要彻底了解现有化合物与DNA结合的机制，这些化合物具有独特类型的特异性。这项研究的长期目标是了解插层反应的分子机制，重点是它们的序列和结构选择性结合的能量基础。一个成功和高效的基础科学项目正在寻求更新，该项目已经为DNA靶向药物开发提供了几个有希望的途径。下一个资助期的研究将侧重于旨在阐明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.高通量竞争透析法的应用和改进，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的结合特性：RNA杂化结构。3.用一种新的量热“Bootprint”方法表征药物的区域选择性结合。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，以及对这种结构选择性的能量基础的描述；2.为指导针对DNA：RNA杂化结构的化合物的合理设计提供基本信息，DNA：RNA杂化结构是一个具有巨大生物学意义的靶标。3.为定量研究药物与DNA之间的相互作用提供了一种新的工具。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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 high- throughput 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. PERFORMANCE SITE ========================================Section End===========================================