STRUCTURAL CHARACTERIZATION OF BOUND 50S RIBOSOMAL INHIBITORS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。Rib-X Pharmaceuticals, Inc.是一家早期制药公司，其目标是通过发现针对核糖体的新型抗感染化学类来解决细菌对当前抗菌剂的耐药性增加所带来的困难。为了缩短药物发现过程，我们采用基于结构的设计策略，利用来自Haloarcula marismortui的50S核糖体的高分辨率晶体结构与小分子抑制剂络合。这些分子的范围从已知的抗生素引线，到基于我们之前的结构结果设计和合成的化合物。由此得到的结构信息将为进一步的化合物设计提供指导，旨在提高结合亲和力和改善整体药物样质量。鉴于我们的50S晶体的非常大的单位胞尺寸和衍射极限，我们不仅限于使用高强度同步加速器源进行x射线，而且还限于在亮度，光束准直和探测器尺寸方面的最佳光束线。

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. Rib-X Pharmaceuticals, Inc. is an early stage pharmaceutical company whose stated goal is to address the difficulties presented by increasing bacterial resistance against current antibacterial agents by discovering novel chemical classes of anti-infectives that target the ribosome. In order to shorten the drug discovery process, we are employing a structure-based design strategy utilizing high resolution crystal structures of the 50S ribosome from Haloarcula marismortui complexed with small molecule inhibitors. These molecules range from known antibiotic leads, to compounds designed and synthesized in-house based on our previous structural results. The resulting structural information will serve as a guide for further compound designs that aim to increase binding affinity and improve overall drug-like qualities. Given the very large unit cell dimensions and diffraction limits of our 50S crystals, we are constrained to use not only a high intensity synchrotron source for x-rays, but are also limited to the best beam lines in terms of brightness, beam collimation and detector size.