PROPRIETARY RESEARCH ON MACROMOLECULES

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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 is a proprietary project involved in drug discovery. The structural results generated by these experiments will be fed back into an iterative structure-based drug design program aimed at developing therapeutics against very aggressive human cancers such as melanoma, breast cancer, and small-cell lung cancer. Rapid design and optimization of the lead compounds in such a drug design cycle is incumbent on timely access to synchrotron sources for the generation of the needed structural data. Many of the crystals diffract very poorly and require very intense beams for timely collection of data. For example, one such project required 5 second exposures per degree of data on X29; this exposure time would be more than a minute per degree at some other lines and would not be a feasible data collection on an in-house source. Prior accomplishments of the PI can be seen in the following representative publications [Bussiere and Bastia, Mol. Microbiol., 31:1611-18 (1999); Bussiere et al., Mol. Cell, 2:75-84 (1998); Bussiere et al., Biochemistry, 37: 7103-12 (1998)]. In addition to the publications listed in the previous section, we have recently written a review on the use of structure-based drug design in the discovery of cancer therapeutics: Knapp et. al. Curr. Top. Med. Chem. 6: 1129-1159 (2006).