Fragment-based approaches to the design of candidate drugs that interrupt protein-protein interactions involved in cell regulation. (360G-Wellcome-080083_Z_06_Z)

Most cell activities are regulated by multiprotein systems, often with three o r more components. Their extensive and rather featureless protein-protein inte rfaces have proved difficult to target with small chemical entities and very f ew drugs have been designed to disrupt them. In the past fifteen years big pha rma has focused on high-throughput screening against very large compound colle ctions (up to 5 x 106), relying on the assumption that great chemical diversit y together with high-throughput technologies would allow exploration of most p ossible chemical combinations quickly. Although most targets have had well def ined pockets in ligand binding or active sites, these developments proved less successful than had been hoped. In response a range of new approaches have at tempted to bring together structure-guided approaches with screening. Among th e most successful have been methods based on identifying small molecular fragm ents (MW <250 Da) which bind weakly to protein targets, and using these as sta rting points for the assembly of more potent inhibitors. In this application w e seek to extend these fragment-based approaches to exploit small pockets in p rotein-protein interfaces, particularly where one component is a flexible poly peptide that assembles to give a specific structure only in the multiprotein c omplex.