Probing class I PDZ domain ligand interaction

Small molecules interacting with proteins to modulate cellular behavior is a model result of drug discovery. The challenges faced when developing a new drug entity involve understanding complex biological mechanisms and transferring this knowledge to a simple logical flow of responses which can then be manipulated by the specific interaction of a small molecule. An outstanding problem in drug discovery is effective manipulation of protein-protein interactions.;PDZ domains, a family of protein domains evolved to bind small sequence specific areas of proteins, represent an interesting area of biology to manipulate. The sole function of PDZ domains seems to be binding short sequences of proteins which suggests that developing a small molecule to bind in the site of interaction would interrupt the PDZ domain's function. Because PDZ domains can bind multiple proteins with varying affinity a PDZ domain inhibitor could result in a complex phenotype by inhibiting all function of a PDZ domain or some level of partial inhibition by differing its affinity.;This thesis describes the development of a small molecule inhibitor of a PDZ domain. Combining work from many labs and collaborators has led to the basic understanding of a PDZ domain function and to the structural understanding of PDZ/peptide interactions at an atomic level. The introduction aims to set the background for the entire research. Advancements have been made in the identification of PDZ domains and understanding of their function and role in a cellular context. Also, much information has been collected about the diverse functions that the interaction between a PDZ domain and its partner protein accomplishes.;Chapter 1 of this thesis describes the initial experiments used to understand the interactions of the PDZ domain. This chapter lays the groundwork for the ensuing experiments and the results of these experiments helped to direct the research.;Chapter 2 describes experiments characterizing a scaffold and its interaction with a PDZ domain. A small library of compounds was synthesized and assayed for its interaction with a PDZ domain. The result of these experiments reveals the utility of this scaffold to create inhibitors for PDZ domains.