Targeting Nucleic Acids with an Integrated Virtual and Actual Screen

描述（由申请人提供）：DNA仍然是小分子治疗剂的代表性不足的靶标。越来越多的证据表明，非B DNA结构在基因表达和端粒功能中起着重要作用。靶向这些结构元件是开发新治疗剂的有吸引力的创新策略。由于许多原因，在这种抗基因策略中使用小分子是有希望的。在基因扩增之前靶向基因以产生多个mRNA和蛋白质分子是有利的，因为有更少的靶点要击中。此外，更容易以化学方式操纵小分子（而不是治疗性DNA或RNA分子）以优化结合和药理学性质。我们寻求更新我们的创新和高效的计划，以开发一个集成的虚拟和实际的筛选平台，用于发现新的先导化合物，选择性地结合到具有生物学意义的独特DNA结构。在最初供资期间取得了显著进展，我们实现了最初提案中提出的大部分具体目标。我们已经发现了几种化合物，选择性地结合到特定的四链体结构，一个强烈的电流感兴趣的目标。我们建议开展研究，继续开发和优化综合筛查平台。在下一个资助期间，我们将专注于发现选择性结合生物学上重要的四链体和DNA-RNA杂交结构的先导化合物。为了做到这一点，我们将开发复杂的四链体结构的结构模型，使用一种新的方法，将分子动力学模拟与严格的实验验证相结合。我们将描述我们在最初的资助期间发现的新型四链体结合剂的生物物理和功能特性。具体目标包括：1.开发和完善虚拟筛选平台。2.开发更高通量的配体结合试验。3.发现与功能重要的核酸结构结合的先导化合物。4.生物物理和生物学特性的新G-四链体结合剂发现在最初的资助期间。拟议的研究将提供一个改进的综合平台，用于发现新的先导化合物，并彻底表征几种新发现的具有独特化学支架的四链体结合剂。

DESCRIPTION (provided by applicant): DNA remains an underrepresented target for small molecule therapeutic agents. There is mounting evidence to indicate that non-B DNA structures play prominent roles in gene expression and in the function of telomeres. Targeting these structural elements is an attractive and innovative strategy for the development of new therapeutic agents. The use of small molecules in such an antigene strategy is promising for many reasons. Targeting the gene before its amplification to produce multiple mRNA and protein molecules is advantageous because there are fewer targets to hit. In addition, is easier to manipulate small molecules (rather than therapeutic DNA or RNA molecules) chemically to optimize binding and pharmacological properties. We seek renewal for our innovative and highly productive program to develop an integrated virtual and actual screening platform for the discovery of new lead compounds that bind selectively to unique DNA structures of biological significance. Progress during the initial funding period was outstanding, and we achieved most of the specific aims proposed in our initial proposal. We have discovered several compounds that bind selectively to particular quadruplex structures, a target of intense current interest. We propose studies that will continue to develop and optimize the integrated screening platform. During the next funding period, we will focus on the discovery of lead compounds that bind selectively to biologically important quadruplex and DNA-RNA hybrid structures. In order to do this, we will develop structural models for complex quadruplex structures using a novel approach that integrates molecular dynamics simulations with rigorous experimental validation. We will characterize the biophysical and functional properties of the novel quadruplex binders we have discovered during the initial funding period. Specific aims include: 1. Development and refinement of the virtual screening platform. 2. Development of higher-throughput assays for ligand binding. 3. Discovery of lead compounds that bind to functionally important nucleic acid structures. 4. Biophysical and biological characterization of novel G-quadruplex binding agents discovered during the initial funding period. The proposed studies will deliver an improved integrated platform for the discovery of novel lead compounds and a thorough characterization of several newly-discovered quadruplex binders with unique chemical scaffolds.