Design of Inhibitors for S100B

韦伯实验室的一项主要工作是研究蛋白质之间的相互作用，目的是抑制它们。结构研究、热力学结合和动态测量用于表征星形细胞蛋白S100B与其生物靶点之一肿瘤抑制蛋白p53之间的钙依赖性相互作用。基于这一信息的抑制剂可能与治疗阿尔茨海默病等疾病中发现的异常细胞生长有关。本研究的重点是将蛋白质动力学纳入S100B抑制剂的设计中。虽然这项研究对S100B抑制剂特别重要，但它也将在一般意义上对基于结构的药物设计有用。Aim 1使用传统的基于结构的方法来识别结合S100B的小分子。这种方法没有考虑到蛋白质的动力学。接下来，通过核磁共振光谱研究负载钙的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方案。通过这种新的对接方法，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）。然后将此搜索的结果与不包含动态数据的对接协议（在Aim 1中）进行比较。最后，将完成药物结合S100B配合物的三维结构和动力学，并与不含药物的配合物进行比较。总之，这些结构和动态数据将使我们能够在下一次药物设计中设计出新的、高亲和力的、抑制S100B功能的小分子。

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.