STRUCTURAL CHARACTERIZATION OF BOUND 50S RIBOSOMAL INHIBITORS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。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。所列机构为中心机构，不一定是研究者机构。Rib-X Pharmaceuticals，Inc.是一家早期制药公司，其既定目标是通过发现靶向核糖体的新型化学类别的抗感染药来解决由增加细菌对当前抗菌剂的抗性所带来的困难。为了缩短药物发现过程，我们采用了基于结构的设计策略，利用来自Haloarcula marismortui的50 S核糖体与小分子抑制剂复合的高分辨率晶体结构。这些分子的范围从已知的抗生素先导化合物到基于我们以前的结构结果内部设计和合成的化合物。所得到的结构信息将作为进一步化合物设计的指导，旨在增加结合亲和力和改善整体药物样质量。由于我们的50 S晶体具有非常大的晶胞尺寸和衍射极限，我们不仅要使用高强度的同步加速器X射线源，而且还要限制亮度、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.