Kinase proteins are intimately involved in cell signalling, and in many cases mutations to these proteins are involved in the development of cancers. A number of small-molecule drugs have been developed to target these proteins, most notably gleevec, which binds to the BCR-ABL kinase and is used as a treatment for chronic myelogenous leukemia, and iressa, which binds to the epidermal growth factor receptor’s (EGFR) tyrosine kinase domain and is used to treat non-small cell lung cancer. However, as is the case for bacteria and viruses, the tumour proteins can mutate and thereby develop resistance to these drugs. The mechanisms by which these mutations confer drug resistance are unclear, and are likely to depend on the particular mutation involved. Clearly, however, if we are able to understand these mechanisms, we are then in a position to design novel inhibitors which are unaffected by these mutations.
In this studentship, you will address the issue of how mutations of EGFR confer drug resistance to kinase inhibitors by using a range of simulation techniques, including docking and scoring, fast free energy calculations, and more accurate rigorous free energy methods. Methods to calculate the relative free energies of different protein conformations will also be used. This studentship is funded by the EPSRC and AstraZeneca (AZ), and will be supported by direct access to relevant experimental data available through AZ. The project will be supervised by Prof Jonathan Essex at the University of Southampton, together with a senior scientist from AZ. You will be joining an established research team working in the area of applying and developing computer simulation methods to biological problems.
should have, or expect to receive shortly, a good degree in chemistry, physics, biochemistry, or a relevant discipline, and a keen interest in molecular modelling. Please contact Dr Richard A Ward (richard.a.ward[ at ]astrazeneca.com) for enquiries related to this project and for further information regarding the nature of this industrially-sponsored studentship.
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