(MRC DTP) Design of allosteric small molecule inhibitors of fibrosis using advanced molecular simulation techniques

Integrins are a family of protein receptors that play a major role in cell survival, growth and migration. Their function is to transmit signals across the cell membrane by undergoing an elegant large scale structural rearrangement. In disease, integrins such as V6, have been linked to a range of pathologies, including cancer metastasis and fibrosis. The aim of this project is to develop compounds which can modulate the allosteric mechanism of V6, to provide a deeper understanding of integrin action as well as a route to studying their effect on liver fibrosis. To achieve this, the project will apply advanced molecular simulation techniques to characterise the allosteric mechanism of V6 and guide the design of small molecule inhibitors. Predicted actives will be procured and experimentally tested for affinity and mode of action. The most promising compounds will be assessed for their anti-fibrotic effect on models of liver fibrosis. Thus, this interdisciplinary project combines computational, chemical, biophysical and biological aspects to offer an exciting research opportunity at the chemical biology interface.

http://research.bmh.manchester.ac.uk/bryce
http://www.manchester.ac.uk/research/karen.piperhanley/
http://www.manchester.ac.uk/research/roger.whitehead/
http://www.manchester.ac.uk/research/paul.mould/