Targeting Nucleic Acids with an Integrated Virtual and Actual Screen

通过集成的虚拟和实际屏幕靶向核酸

• 批准号: 8827793
• 负责人: Jonathan B. CHAIRES
• 金额: $ 32.52万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827793
• 关键词: Active Sites; Antineoplastic Agents; Area; Beryllium; Binding; Biological; Biological Assay; Chemicals; Complex; Computer Simulation; DNA; DNA Structure; Detection; Development; Dialysis procedure; Drug Targeting; Elements; Fluorescence; Fluorescence Resonance Energy Transfer; Funding; G-Quartets; Gene Expression; Gene Targeting; Genome; Hybrids; Indium; Intercalating Agents; Label; Laboratories; Lead; Libraries; Ligand Binding; Ligands; Measures; Messenger RNA; Methods; Modeling; Nucleic Acid Binding; Nucleic Acids; Oncogenes; Pharmaceutical Preparations; Play; Property; Proteins; RNA; RNA-Directed DNA Polymerase; Role; Specificity; Structural Models; Structure; Telomerase; Telomere Maintenance; Temperature; Therapeutic Agents; Validation; Work; antigene; c-myc Genes; cancer cell; high throughput screening; improved; innovation; interest; melting; molecular dynamics; novel; novel strategies; novel therapeutics; nucleic acid structure; overexpression; programs; promoter; quadruplex DNA; receptor; scaffold; screening; small molecule; telomere; therapeutic DNA; therapeutic RNA; virtual

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.

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发挥着重要作用。针对这些结构元件是开发新治疗剂的一种有吸引力且创新的策略。出于多种原因，在这种反基因策略中使用小分子是有希望的。在扩增之前靶向基因以产生多个 mRNA 和蛋白质分子是有利的，因为要击中的目标较少。此外，更容易化学操作小分子（而不是治疗性 DNA 或 RNA 分子）以优化结合和药理学特性。我们寻求更新我们的创新和高效计划，以开发一个集成的虚拟和实际筛选平台，用于发现选择性结合具有生物学意义的独特 DNA 结构的新先导化合物。最初资助期间的进展非常出色，我们实现了最初提案中提出的大部分具体目标。我们发现了几种选择性结合特定四链体结构的化合物，这是当前人们强烈关注的目标。我们提出的研究将继续开发和优化综合筛选平台。在下一个资助期间，我们将专注于发现选择性结合具有重要生物学意义的四链体和 DNA-RNA 杂合结构的先导化合物。为了做到这一点，我们将使用一种将分子动力学模拟与严格的实验验证相结合的新方法来开发复杂四联体结构的结构模型。我们将表征我们在初始资助期间发现的新型四联体粘合剂的生物物理和功能特性。具体目标包括： 1. 虚拟筛选平台的开发和完善。 2. 开发更高通量的配体结合检测方法。 3. 发现与功能上重要的核酸结构结合的先导化合物。 4. 初始资助期间发现的新型 G-四链体结合剂的生物物理和生物学表征。拟议的研究将为发现新型先导化合物提供一个改进的综合平台，并对几种新发现的具有独特化学支架的四联体结合物进行彻底表征。