PhD Studentship in the Computational Investigation of Drug Resistant Mutations in the Kinases

PhD Studentship [3 y; good degree (or expect to receive
shortly) in chemistry, physics, biochemistry or a relevant discipline;
keen interest in molecular modelling; "Comp Investigation of Drug
Resistant Mutations in the Kinases"] / University of Southampton


PhD Studentship in the Computational Investigation of Drug Resistant Mutations in the Kinases
Academic Supervisor: Professor Jonathan W. Essex, School of Chemistry, University of Southampton.
Industrial Supervisor: Dr Richard A Ward, AstraZeneca, Alderley Park, Macclesfied.
36 Month PhD Studentship
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.
Applicants
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@astrazeneca.com)
for enquiries related to this project and for further information
regarding the nature of this industrially-sponsored studentship.