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The Washington Research Foundation Fellowship

Sara Calhoun - Bioengineering - 2009-10 WRFF

Buckley Kate photoOnce I entered the undergraduate program in the Department of Bioengineering, I was eager to begin participating in research that integrates new technology and biology. During the summer after my sophomore year, I began performing research in Professor Valerie Daggett’s lab. The Daggett Lab performs molecular dynamics simulations of proteins and applies computational approaches to investigate biomedical problems on the molecular level. In the lab, I have participated in projects at different points in the development of methods for rational drug design. My experience working in the Daggett Lab has enhanced my interest in solving medical problems from a computational approach. After graduation, I intend to continue my research with Professor Daggett as I apply to graduate programs in computational biology. My hope is to contribute to the biomedical sciences through a long-term career in research. I am grateful for the funding provided through the WRFF and the support to achieve my goals.

Mentor: Valerie Daggett, Bioengineering

Project Title: Design of Small Molecule Drug for the Rescue of p53 Tumor Suppresor Mutants

Abstract: The tumor suppressor p53 is a transcription factor involved in many important signaling pathways, such as apoptosis and cell-cycle arrest. Over half of human cancers lose p53 function by a single nucleotide mutation in its gene. Although structures of some p53 mutants have not been determined experimentally due to low structural stability, the structural effects of a single amino-acid change can be predicted using molecular dynamics (MD) simulations. Different single amino-acid changes in the core domain of the protein result in a variety of structural changes. Previous experimental studies suggest that p53 mutants that affect the overall stability are potential targets for drug rescue by a small molecule drug. Using computational structure-based drug design, an anticancer drug will be developed to target p53 mutants and rescue their function by stabilizing the protein structure. Virtual screening of a small molecule database can be used to limit the number of potential drug candidates. Docking runs can be used to determine drug candidates with the most potential for targeting p53 mutants. Docking programs are useful to find the most energetically favorable binding modes and calculating the binding energies of a molecule to the protein. Simulations of p53 mutants bound to drug compounds that are selected after virtual screening, and experimental work will validate the results of the simulations. Based on simulations and experiments, modifications will be made to the designs in order to improve binding affinity and its effectiveness in stabilizing the protein structure. After a series of modifications and evaluations, the goal is to produce a final drug design that will bind p53 mutants with high affinity and improve the overall thermodynamic stability of p53 mutants.