Protein Peptide Interactions

Our areas of interest are focused mainly in the areas of drug discovery and in studying ligand/peptide protein interactions in particular. To pursue these aims we currently study several target systems such as eIF4E and MDM2, which are both well-validated cancer drug targets, amongst others. For both these targets we pursue small molecule and peptidomimetic approaches using a structure based drug design approach coupled to fragment and virtual screening approaches. In collaboration with the Verma group, located in BII here at Biopolis, computational techniques are also being applied to studying the interactions important at the interfaces involved in recognizing peptides and small molecules and how they can be used to design more potent binders. It is hoped that this combination of approaches can lead to successful drug design.

As an example of the work undertaken in the lab we have used crystallography to isolate several different poses of the cap-binding site in eIF4E in complex with the eIF4GI peptide. In conjunction with phage display selections against eIF4E we are using this information to drive a tandem approach to discovering more potent binders against this protein. These approaches consist of using the nature of the conformational changes identified using crystallography to refine virtual screening programs against the cap-binding site and using information derived about the peptide in the same experiments as the basis for a complementary peptidomimetic approach. The peptidomimeic approach in this case is focused in trying to stabilize the alpha-helix in the peptide to reduce the entropy of binding and generate a more strongly interacting molecule. Phage display has proven useful in driving this approach. Techniques used in this work also encompass ITC, Fluorescence scanning fluorimetry and circular dichroism.