Structure-Based Design of Molecules to Reactivate Tumor-Derived p53 Mutations
Annual rept. 5 May 2005-4 May 2006
PENNSYLVANIA UNIV PHILADELPHIA WISTAR INST
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Of the genetic alterations associated with breast cancer, changes in p53 are the most frequently identified and a subset of these changes destabilizes the p53 core domain structure. The overall goal of our studies is to identify small molecule compounds that bind and stabilize this subset of tumor-derived p53 mutants. We anticipate that the identification of such compounds will serve as a scaffold for the preparation of small molecule drugs for the treatment of p53-mediated breast cancer. Towards this goal, we have employed a Multiple Solvent Crystal Structures MSCS technique to identify a p53 binding sites for the small molecule compound tris hydroxymethylaminomethane Tris and have used both solution studies and molecular dynamics simulations to show that Tris binding increases the stability of the p53 core domain. We have also carried out virtual screening in silico to identify Tris analogues that are predicted to have improved p53 core domain binding and stability properties. In the coming year, we will continue the virtual screening studies and test our virtual screening hits in solution for improved p53 core domain binding and stability. We will also cocrytallize the p53 core domain with the Tris analogues that show the most favorable properties for second generation structure-based optimization of these compounds.
- Anatomy and Physiology
- Medicine and Medical Research