Design of Inhibitors for S100B

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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.