Design of Inhibitors for S100B

S100B抑制剂的设计

• 批准号: 6487609
• 负责人: JOSEPH MARKOWITZ
• 金额: $ 2.67万
• 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/6487609
• 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.

韦伯实验室的一项主要工作是研究蛋白质之间的相互作用，以抑制它们。 结构研究与热力学结合和动态测量一起用于表征星形细胞蛋白 S100B 与其生物靶标之一肿瘤抑制蛋白 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。 该提案的重点是将蛋白质动力学纳入 S100B 抑制剂的设计中。 虽然这项研究对于 S100B 抑制剂特别重要，但它对于一般意义上的基于结构的药物设计也很有用。 目标 1 使用传统的基于结构的方法来识别结合 S100B 的小分子。该方法没有考虑蛋白质的动力学。 接下来，将通过核磁共振波谱研究负载钙的 S100B 的主链和侧链动力学。 在目标 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，该搜索的结果将与不包含动态数据的对接协议（目标 1）进行比较。最后，将完成药物结合的 S100B 复合物的 3D 结构和动力学，并与没有药物的情况进行比较。总之，这些结构和动态数据将有助于设计新的、亲和力更高的小分子，从而在下一次药物设计迭代中抑制 S100B 功能。