SCREENING FOR FUNCTIONAL BINDING EVENTS WITH WAXS

用蜡筛选功能结合事件

• 批准号: 8168620
• 负责人: LEE MAKOWSKI
• 金额: $ 0.54万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168620
• 关键词: Affect; Binding; Chemicals; Clinical; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Drug Delivery Systems; Event; Funding; Future; Goals; Grant; Industry; Institution; Libraries; Ligand Binding; Ligands; Methods; Pharmacologic Substance; Proteins; Publishing; Research; Research Personnel; Resources; Scientist; Screening procedure; Solutions; Source; Structure; Testing; Therapeutic; United States National Institutes of Health; Work; drug discovery; expectation; novel; research study; small molecule; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is a collaborative effort between industry and Argonne staff to develop a novel drug discovery tool using the high flux x-rays at the APS. The goal is to develop a quick screen to identify functional interactions of small molecules with proteins. Small-molecule ligands that change the structure of a protein are likely to affect its function, whereas those causing no structural change are less likely to be functional. Wide-angle x-ray scattering (WAXS) can easily be carried out on proteins and small molecules in solution in the absence of chemical tags or derivatives. We have demonstrated that WAXS is a sensitive probe of ligand binding to proteins in solution and can distinguish between nonfunctional and productive binding (Fischetti et al., 2004; Rodi et al., 2007). The experiments proposed here will be the first extensive test of this method with clinical protein drug targets and a library of pharmaceutical compounds - both validated as active and others with no expected activity. These first experiments will involve screening of well characterized drug targets and compounds and represent a true proof of concept for the use of WAXS as a drug discovery tool. The work is a collaboration between scientists at Argonne, Shamrock Structures, and Zenobia Therapeutics. The results of these experiments will be published. If successful, extensive future work is anticipated with the expectation that some of that work will be proprietary.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目是工业界和阿贡工作人员之间的合作成果，旨在利用 APS 的高通量 X 射线开发一种新型药物发现工具。 目标是开发一种快速筛选方法来识别小分子与蛋白质的功能相互作用。 改变蛋白质结构的小分子配体可能会影响其功能，而那些不引起结构变化的小分子配体则不太可能发挥功能。在没有化学标签或衍生物的情况下，可以轻松地对溶液中的蛋白质和小分子进行广角 X 射线散射 (WAXS)。我们已经证明，WAXS 是配体与溶液中蛋白质结合的敏感探针，可以区分非功能性结合和生产性结合（Fischetti 等，2004；Rodi 等，2007）。 这里提出的实验将是对该方法的首次广泛测试，其中包括临床蛋白质药物靶点和药物化合物库——两者均被验证为具有活性，而其他则没有预期的活性。 这些首批实验将涉及筛选明确表征的药物靶点和化合物，并代表使用 WAXS 作为药物发现工具的真正概念证明。 这项工作是阿贡国家实验室、Shamrock Structures 和 Zenobia Therapeutics 的科学家之间的合作。 这些实验的结果将被公布。 如果成功，预计未来将开展大量工作，其中一些工作将是专有的。