Identification of chemical probes for ionotropic glutamate receptors

We have an exciting opportunity for a talented, highly motivated scientist with a strong background in organic chemistry to join our centre to study for a DPhil.

Project outline
Ligand-gated ion channels are cell surface proteins that play an important role in fast synaptic transmission and in the modulation of cellular activity. Glutamate receptor ion channels, in particular, mediate excitatory responses at the majority of CNS synapses and transduce the binding of a glutamate into an electrical current on a microsecond timescale. They are the only ligand-gated ion channels (LGIC) for which multiple high-resolution crystal structures have been solved. While our understanding of LGICs has significantly progressed during the past decade, many properties of these proteins are still poorly understood, in particular their modulation by allosteric effectors.
Of the three classes of ionotropic glutamate receptors, NMDA and AMPA receptors have been studied extensively and molecules have entered clinical evaluation for negative allosteric modulators and positive allosteric modulators respectively, although neither class has yet delivered a molecule beyond Phase II. Across the wide range of subunit combinations, there is a dearth of chemical tools to enable the roles of the various receptors to be better understood.

Objective
Develop biophysical techniques (crystallography / NMR etc) to screen for positive and negative allosteric modulators of ionotropic glutamate receptor subtypes acting at the extracellular ligand binding or amino terminal domains as enabling tools for both discovery biology and drug discovery. The probability of success is high given the precedent established in house for AMPA receptors, however the lack of tools available for specific NMDA / kainate receptor subtypes will mean that their disclosure should lead to a series of high impact publications. Subsequent fragment optimisation and medicinal chemistry exploration to establish validity of chemical hits, and detailed biophysical characterisation in collaboration with Dr Andrew Penn, University of Sussex.

Training
The student will have the opportunity to develop biochemical and biophysical screening techniques and design and synthesise potential tool inhibitors. The student will develop or acquire skills in chemo informatics, biochemical screening and synthetic chemistry. The student will work in academic labs alongside experienced post-doc scientists and have day-today exposure to diverse drug discovery projects. They will receive training in state-of-the-art computational, screening and synthetic techniques, and will also benefit from close interactions with clinical and structural & discovery biology collaborators. Visits to other groups around UK running NMR fragment screens (industry + academic) along with potential visits to collaborators in US doing electrophysiology characterization may be possible. It is expected for the student to attend 1 UK conference / year + 1 international conference in 3rd year.

Sussex Drug Discovery Centre
The Sussex Drug Discovery Centre (SDDC) is a fully integrated group of drug discovery scientists, equipped with industry standard equipment and capabilities, based at the University of Sussex. Our goal is the discovery of novel therapeutics for diseases with high unmet medical need.

The core aim of the centre is to deliver mature drug discovery assets for subsequent partnering and onward development.
We also play a strong role in the delivery of new chemical probes to assist target validation, particularly through our PhD studentship projects.

In addition to delivering and enabling novel therapeutics, the group aims to play a key role in training the next generation of potential drug discoverers - the extensive experience and expertise within the SDDC is, via PhD studentships and establishing vocational courses within the University, being used to achieve this important goal.

To be considered for a place you will need to complete our online application which can be found at http://www.sussex.ac.uk/study/phd/apply and apply for the generic PhD in Biochemistry.

Apply for 2017 entry, September start. Mention the name of the supervisor in ‘“suggested supervisor’” section. In funding section mention sponsored. In ‘Award details’ mention University of Sussex (School of Life Sciences) funded studentship.

Documents required: A brief statement of interest in the project (upto 2 pages), full CV, two academic references, UG/PG transcripts and IELTS/TOEFL results if you are residing in EU.