Integrated Structural Analysis of Ligand Mimics

The ability to create compounds which can exert a direct and specific therapeutic effect oncellular proteins involved in cancer is of great national importance. In order for a cancer drug to beeffective, it must be specific for a protein involved in the disease process. We will address both of themajor problems associated with developing such useful drugs. The first concern is the selection ofcandidate compounds targeted against proteins involved in the disease process, and the second concernis the techniques to derive structural information sufficient to produce a mimic which meets all thestringent requirements of a useful drug. We will simultaneously address both of these concerns bydesigning a process for the identification of ligand mimics based on the selection of constrained peptidesby an immobilized target receptor, which can be integrated with a new high speed structural method.Specifically, we will identify and determine the structure of specific legend mimics for a cell surfaceprotein involved in human cancers, human Notch. We are able to produce this solution by taking a novelinterdisciplinary approach, combining expertise in NMR, molecular dynamics and molecular biology.