Download Identification of chemical probes for ionotropic glutamate receptors

School funded PhD studentship in Life Sciences
Deadline: 31st January
Prof Simon Ward
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.
UK and EU residents:
The residence eligibility criteria should be satisfied in full if all of the following conditions are met:
(a) the candidate is settled in the UK i.e. is ordinarily resident in the UK without being subject under
the immigration laws to any restriction on the period for which they may stay in the UK;
(b) the candidate has been ordinarily resident in the UK and Islands for three years prior to the date
of start of their course;
(c) no part of the period of residence in (b) was wholly or the purpose of receiving full-time
education
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/pg/applying/ 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.