PROPRIETARY RESEARCH ON MACROMOLECULES

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。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这是一个涉及药物发现的专有项目。 这些实验产生的结构结果将被反馈到一个迭代的基于结构的药物设计程序中，该程序旨在开发针对非常侵袭性的人类癌症（如黑色素瘤、乳腺癌和小细胞肺癌）的治疗方法。 在这样的药物设计周期中，先导化合物的快速设计和优化必须及时获得同步加速器源以生成所需的结构数据。 许多晶体的反射性能非常差，需要非常强的光束才能及时收集数据。 例如，一个这样的项目需要在X29上每度数据曝光5秒;在其他一些线路上，这个曝光时间将超过每度1分钟，并且在内部源上不可行。 PI的先前成就可见于以下代表性出版物[Bussiere和Bastia，Mol.微生物学：31：1611-18（1999）; Bussiere等人，摩尔Cell，2：75-84（1998）; Bussiere等人，Biochemistry，37：7103-12（1998）]。 除了上一节列出的出版物，我们最近写了一篇关于在癌症治疗发现中使用基于结构的药物设计的综述：克纳普等。Curr. Top. 6：1129-1159（2006）。

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).