Molecular Pharmacology PhD

Around a third of all currently approved drugs target G protein-coupled receptors (GPCRs), making these receptors the most successful drug target in history. Our research is focused on the structure and function of GPCRs and understanding the signalling pathways that are important for different physiological and pathophysiological responses.

OVERVIEW

Our PhD programmes offer training in all aspects of molecular pharmacology and our large internationally recognised research group have significant expertise in pharmacological analyses, cell signalling, drug discovery and use of a extensive range of transgenic and disease mouse models to define the physiological functions and therapeutic potential of specific G protein-coupled receptors (GPCR) subtypes.

GPCRs are the largest family of cell surface receptors and are involved in the regulation of nearly every mammalian cellular response. Around a third of all currently approved drugs target GPCRs, making these receptors the most successful drug target in history.

Our research is focused on the structure and function of GPCRs and understanding the signalling pathways that are important for different physiological and pathophysiological responses. We employ wide-ranging and multi-disciplinary approaches to take a ‘molecule to behaviour’ approach to understand, validate and then translate therapeutic opportunities by targeting trans-plasma membrane and intracellular signalling pathways. We identify unique small molecule ligands that modulate cellular signalling cascades and exploit these to define both underpinning biology and their effects on disease progression and remission.

We have driven understanding and therapeutic validation of previously poorly understood and ‘hard to target’ G protein-coupled receptors that are activated by metabolic intermediates, particularly fatty acids of varying chain length. We are established as ‘world-leading’ in areas at the interface so created between metabolism and immunity. This has resulted in ‘spin out’ in 2015 of the company Caldan Therapeutics, which garnered £4.5 million in Series A funding, and in Milligan being a finalist in the 2016 BBSRC ‘Innovator of the Year’ competition. Moreover, our expertise in this area has resulted in the establishment of new links to companies including Heptares Therapeutics and Galapagos NV, as well as consolidating links to the pharmaceutical giant AstraZeneca, resulting in enhanced funding and joint publications.

By linking small molecule ligands, the new wealth of information on structural characteristics of G protein-coupled receptors, and a prion-based model of neurodegenerative disease that displays impaired cognition, Tobin and Bradley have unequivocally established that selective activation of the M1 muscarinic acetylcholine receptor not only improves cognition, a key requirement for any new therapy designed to treat the cognitive decline associated with progression of Alzheimers dementia, but also may actually slow neurodegenerative progression. This work is linked directly to studies being conducted by the pharmaceutical company Eli Lilly. An approach within these studies of generating mouse transgenic ‘knock-in’ lines of receptors modified to act as ‘Designer Receptors Exclusively Activated by Designer Drugs’ has not only been integral to these studies but has inspired the group to broaden this approach to the type of ‘hard to target’ G protein-coupled receptors, a concept developed and reduced to practice by Hudson and Milligan for free fatty acid receptor 2.