SCREENING FOR FUNCTIONAL BINDING EVENTS WITH WAXS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目是工业和阿贡员工之间的合作努力，以开发一种使用APS的高通量X射线的新型药物发现工具。其目标是开发一种快速筛查，以确定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，而那些不会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)可以在没有化学标记或衍生物的情况下很容易地对溶液中的蛋白质和小分子进行测量。我们已经证明WAXS是一种敏感的配体与溶液中蛋白质结合的探针，可以区分非功能性结合和生产性结合(Fischetti等人，2004；Rodi等人，2007)。这里提出的实验将是对这种方法的第一次广泛测试，使用临床蛋白质药物靶标和药物化合物库-两者都被验证为有效的，其他的没有预期的活性。这些第一批实验将涉及筛选具有良好特性的药物靶标和化合物，并代表着将WAXS用作药物发现工具的真正概念证明。这项工作是Argonne、三叶草结构公司和泽诺比亚治疗公司的科学家合作完成的。这些实验的结果将会公布。如果成功，预计未来将进行广泛的工作，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.