Development of fast NMR methods for structure-based drug design

Fragment-based drug design (FBDD) is a technique that has been developed for the rapid and efficient identification of key building-blocks for drug development. FBDD relies on the measurement of interactions between a therapeutic target and small molecular ‘fragments’ that are not, in themselves, candidate drug molecules but represent pieces of the sorts of chemical entities commonly found in drugs. Determining the structure of these fragments in complex with the target protein provides critical information for assembly of the fragments into potent drug candidates. The structures of fragments bound to their target proteins are normally obtained using X-ray crystallography.

However, many drug targets are not amenable to this approach. Although NMR spectroscopy can also be used to determine structures of complexes, it is generally regarded as being too slow to support programs of structure-based drug design. In this project you will develop techniques to enable rapid structure determination by NMR. These will exploit recent advances in protein expression, selective isotope labelling, non-uniform acquisition and conjugation with paramagnetic lanthanides and be applied to therapeutically relevant proteins that are not amenable to crystallography.