Design of Inhibitors for S100B

S100B抑制剂的设计

• 批准号: 6626233
• 负责人: JOSEPH MARKOWITZ
• 金额: $ 2.91万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-24 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6626233
• 关键词: Alzheimer's disease; astrocytes; conformation; drug design /synthesis /production; enzyme structure; fluorescence spectrometry; inhibitor /antagonist; nerve /myelin protein; neural growth associated protein; neuropharmacology; nuclear magnetic resonance spectroscopy; p53 gene /protein; protein protein interaction; protein structure function; thermodynamics

A major effort in the Weber laboratory is to study protein-protein interactions with the goal of inhibiting them. Structural studies, together with thermodynamic binding, and dynamic measurements are used to characterize the calcium-dependent interaction between S100B, an astrocytic protein, and one of its biological targets, the tumor suppressor protein, p53. An inhibitor based on this information could be relevant to treating aberrant cell growth found in diseases such as Alzheimer's disease. The focus of this proposal is to incorporate protein dynamics into the design of S100B inhibitors. While this study is particularly important for S100B inhibitors, it will also be useful in a general sense for structure-based drug design. Aim 1 uses traditional structure-based methods to identify small molecules that bind S100B. This method does not take into account the protein's dynamics. Next, the backbone and sidechain dynamics of calcium-loaded S100B will be studied by NMR spectroscopy. In Aim 2, the dynamics of calcium- bound S100B will be used into our small molecule docking protocol. With this new docking method, the structure and dynamics of calcium- bound S100B will be used to identify small molecules (i.e., drugs) that bind S100B. The results from this search will then be compared to the docking protocol (in Aim 1)that does not include the dynamic data. Lastly, the 3D structure and dynamics of drug-bound S100B complexes will be completed and compared to those done without the drug. Together, these structural and dynamic data will enable the design of new, higher affinity, small molecules that inhibit S100B function in the next iteration of drug design.

韦伯实验室的主要努力是研究蛋白质 - 蛋白质相互作用，以抑制它们。 结构研究以及热力学结合以及动态测量可用于表征S100B，星形胶质细胞蛋白及其生物学靶标之一，肿瘤抑制蛋白p53之间钙依赖性的相互作用。 基于此信息的抑制剂可能与治疗在阿尔茨海默氏病这样的疾病中发现的异常细胞生长有关。 该建议的重点是将蛋白质动力学纳入S100B抑制剂的设计中。 尽管这项研究对于S100B抑制剂尤为重要，但在基于结构的药物设计的一般意义上，它也将很有用。 AIM 1使用传统的基于结构的方法来识别结合S100B的小分子。该方法没有考虑到蛋白质的动力学。 接下来，将通过NMR光谱研究研究钙加载的S100B的主链和侧链动力学。 在AIM 2中，钙结合S100B的动力学将用于我们的小分子对接协议。使用这种新的对接方法，钙结合S100B的结构和动力学将用于识别结合S100B的小分子（即药物）。 然后将将此搜索的结果与不包括动态数据的对接协议（在AIM 1中）进行比较。最后，将完成与没有药物的药物进行的3D结构和动力学。总之，这些结构和动态数据将实现新的，更高亲和力的小分子的设计，这些分子抑制S100B在下一迭代中的功能。