Molecular and in-silico approaches to understanding intracellular allosteric modulation at the CXC chemokine receptor 2 (CXCR2)

The Universities of Nottingham and Monash have developed a PhD programme at the cutting edge of molecular pharmacology and drug discovery and are recruiting exceptional calibre applicants of any EU nationality for a 4-year research programme including a full year of study at Monash University, Australia.


Background: Chemokines are critical messengers involved in inflammation, and their receptors are of great interest in drug discovery, as targets for inflammatory disease (e.g. asthma and chronic obstructive pulmonary disease) and in hijacking the immune system to treat cancer. One issue for drug development around these receptors is that the native chemokine ligands are large peptides whose binding is difficult to replicate with small molecules. However an alternative strategy is to design molecules that influence receptor function by interacting with a different allosteric site from the chemokine. A group now at Nottingham (ref 1) was one of the first to describe such molecules for one of the key chemokine receptors, CXCR2, and demonstrate an unusual binding site located at the interface between the receptor and its signalling effector proteins. Since this discovery, similar intracellular allosteric binding sites have been identified structurally in other receptors (e.g. 2-adrenoceptor, CCR2, CCR9– refs 2 - 4), that all belong to the G protein-coupled receptor (GPCR) family – suggesting that intracellular allosteric modulators may soon become a widespread approach in targeting these receptors.

However, we know little about how this class of allosteric ligands affects GPCR function in molecular terms, and in particular whether selectivity for different types of downstream signalling can be achieved (e.g. via G proteins and arrestins). Better structure activity relationships (SARs) at this binding site, for example focussed on CXCR2, have a real potential to reveal new ligand classes – for example “biased” modulators that selectively regulate particular signalling protein interactions to tune the functional chemokine response. However the development of good allosteric SAR is often limited by the poor range of compound analogues and the lack of suitable probes to monitor binding at the target site directly.

Aims and project plan: You will design, synthesise and pharmacologically characterise a library of small molecule ligands to further explore the allosteric SAR at the CXCR2 receptor intracellular modulator site. You will also take the lead in guided design of molecules through computational modelling studies and their refinement. This platform will also allow you to develop novel fluorescent high affinity ligands for CXCR2, and use them to monitor ligand binding and kinetics by our established methods (ref 5). In conjunction with a second pharmacology-focused studentship underway at Nottingham, you will advance our understanding of the nature of GPCR allostery at this intracellular site, and how allosteric ligands influence both chemokine messenger and effector protein binding to tune CXCR2 signalling. In due course, your data will also inform future drug discovery projects focused on CXCR2 allosteric ligands.

Student training and skills: This chemical biology-focused project will span the disciplines of synthetic chemistry, computational modelling and pharmacology to increase our understanding of CXCR2 biology. You will also work closely with a team including other groups in the School of Life Sciences, and a second molecular pharmacology student. With increasing numbers of allosteric ligands being discovered for the wider GPCR family, the results will be of direct relevance to many other important receptors.

Timescale: The student will spend the first 2 years in Nottingham, based at the Centre for Biomolecular Sciences dedicated research facility, located on our attractive University Park Campus and Cell signalling research laboratories housed in the Queens Medical Centre. The student will then spend a year in Monash University at the Monash Institute of Pharmaceutical Sciences (MIPS), Australia under the supervision of internationally leading research collaborators. The final year of the PhD will be spent back at Nottingham University and will culminate in the submission of the doctoral thesis.

Application Process: Applicants with a background in synthetic organic chemistry, medicinal chemistry and computational chemistry are encouraged to apply. Informal enquiries should be directed to the project supervisors listed below and we will be happy to provide further information and detail the formal application process.

Dr. Shailesh Mistry ([Email Address Removed])
Prof. Charles Laughton ([Email Address Removed])
Dr. Nicholas Holliday ([Email Address Removed])