Fragment-based development of protein-protein interaction inhibitors

In this large collaboration we are establishing fragment based drug discovery methods from library handling, screening, biophysical characterisation and structural biology through to chemical synthesis of new compounds. We are targeting a traditionally difficult class of drug targets, namely protein-protein interactions. These are challenging targets as typical interaction site is large and relatively flat, lacking the three dimensional features associated with enzyme active sites and other small molecules binding sites typically targeted by drug developers. One of the key challenges we face in this area is to keep the size of the inhibitor small while achieving high potency.

We use a number of complementary biophysical techniques both to screen the fragment libraries and to validate the fragments that have been identified in the initial screen. Structural biology is a key to fragment based approach and we make extensive use of X-ray crystallography to analyse the molecular details of the fragment-protein complexes to guide computational and synthetic design of higher potency chemicals.

As a model system we are targeting the interaction between human recombinase RAD51 and breast cancer associated proteins BRCA2. This interaction is essential for homologous recombination in humans and mutations affecting this predispose people to breast and other cancers. Inhibition of this pathway can lead to more effective therapies for the treatment of various other cancers too.