Abstract

Structural Biology and Drug Discovery: Targeting Protein-Protein Interfaces

Sir Tom Blundell, Professor, University of Cambridge

Given that gaining selectivity in the design of chemical tools and therapeutic agents has proved harder to achieve with members of large superfamilies such as kinases, interest is increasingly focusing on targeting the protein-protein interfaces of multiprotein assemblies that regulate them. Evidence is accumulating that such an approach will offer greater opportunities of improving specificity and selectivity. However, at the same time they pose new challenges, particularly because the protein-protein interfaces tend to be less “druggable” than active sites, and the hydrophobic nature of interactions in most protein-protein interfaces leads often to large lipophilic molecules. I will describe computational analyses of protein interface landscapes for multiprotein assemblies involving both globular domains and more flexible loops and peptides that interact through concerted folding and binding. I will exemplify the use of fragment-based approaches on two very different targets: (1) Rad51 interactions with BRCA2 in homologous recombination, involving concerted folding and binding of flexible repeat regions of BRCA2, and (2) the interactions of the Met Receptor with HGF/SF and the secondary receptor heparan sulphate.