SCREENING FOR FUNCTIONAL BINDING EVENTS WITH WAXS

Illinois Institute Of Technology, Chicago IL

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Abstract

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.