Target validation and drug discovery for the Free Fatty Acid family of G protein-coupled receptors

PhD Supervisor: Professor Graeme Milligan and Dr Lynda Williams

Summary of project: Five distinct G protein-coupled receptors recognise and respond to free fatty acids of varying chain length. In each case they have been suggested to be involved in processes that become ineffective during the development of metabolic disorders including diabetes (FFA1, FFA2, GPR120) or may counter low level chronic inflammation that is believed to underpin the development of diabetes (FFA2, FFA3, GPR84, GPR120). Despite the high level of interest engendered by these observations and the recent demonstration that dysfunction of GPR120 leads to obesity in both mouse and human, with the exception of FFA1 where an agonist compound produced by the pharmaceutical company Takeda is currently in phase III clinical trials, these receptors remain poorly characterised and validated as therapeutic targets. In part this is due to a lack of selective and potent ligands. We currently have an extensive medicinal chemistry programme designed to both develop novel agonist and antagonist ligands for each of these receptors as well as to synthesise patented ligands as reference compounds and to use these to understand the binding pocket(s) in each receptor. This will allow the development of further improved ligands. We also examine function of these receptors in animal models of obesity and metabolic disorders and have expertise in dietary control and supplementation with ligands that activate these receptors including omega fatty acid-rich fish oils known to have protective value. The project will thus characterise the detailed molecular pharmacology of a range of novel compounds for these receptors using combinations of homology modelling, mutagenesis, species orthologue selectivity assessments and cellular signalling assays and, once fully characterised, use the best exemplars in a range of both ex vivo and in vivo assays designed to validate each of these family members as being relevant as therapeutic targets to potentially treat metabolic disorders, control satiety and reduce body weight.

This PhD studentship is funded by MSD, The Scottish Funding Council (SFC) and the University of Glasgow. As part of an on-going legacy to Scottish life sciences, MSD, a global healthcare leader working to make the world be well, has given a substantial monetary funding to the Scottish Funding Council (SFC) for distribution via SULSA to develop and deliver a high quality drug discovery research and training programme. SULSA is an SFC funded strategic research pooling partnership among the top six Scottish Universities in the Life Sciences: Aberdeen, Dundee, Edinburgh, Glasgow, St Andrews and Strathclyde.

This PhD will benefit from a high-quality training programme, travel and consumables budgets, as well being integrated into the SULSA network of excellence. All aspects of the programme have been geared towards attaining the highest value in terms of scientific discovery, training and impact.

Applications are invited from outstanding UK and EU students, who hold or expect to gain a first or upper second-class degree or equivalent. The closing date for applications is 15th June 2012. Successful candidates will receive an annual stipend in line with RC-UK rates and payment of their tuition fees. This studentship will start in October 2012.