SCREENING FOR FUNCTIONAL BINDING EVENTS WITH WAXS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 该项目是行业和阿贡工作人员之间的合作努力，以开发一种新的药物发现工具，使用高通量X射线在APS。 目标是开发一种快速筛选方法，以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具有功能。广角X射线散射（WAXS）可以很容易地在没有化学标签或衍生物的情况下对溶液中的蛋白质和小分子进行分析。我们已经证明WAXS是配体与溶液中蛋白质结合的灵敏探针，并且可以区分非功能性结合和生产性结合（Fischetti等人，2004; Rodi等人，2007年）。 本文提出的实验将是该方法与临床蛋白质药物靶点和药物化合物库的第一次广泛测试-两者均被验证为活性和其他无预期活性。 这些第一批实验将涉及筛选表征良好的药物靶点和化合物，并代表了WAXS作为药物发现工具的真正概念证明。 这项工作是阿贡，三叶草结构和Zenobia治疗学的科学家之间的合作。 这些实验的结果将被发表。 如果成功的话，预计未来将开展大量工作，其中一些工作将是专有的。

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.