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MRC DiMeN Doctoral Training Partnership: Software, Synthesis and Screening: cheminformatic led invention, design and synthesis of novel compounds for the treatment of septic shock


Project Description

Industrial and academic medicinal chemists take advantage of modern cheminformatic and biology technologies to inform and guide their science. Collaboration across disciplines is essential, so synthetic chemists work seamlessly with biologists and software engineers when searching for active pharmaceutical compounds. This project, a collaboration between Professor Joe Harrity, Redbrick Molecular Ltd and the Medicines Discovery Catapult, has several strands that underpin the key skills and experiences required of a modern day drug discovery scientist. You will develop synthetic chemistry skills to synthesise novel molecules for drug screening in the search for a treatment for septic shock. You will also utilise cheminformatics and machine learning techniques to predict activity and to select priority molecules for your synthesis work.

Septic shock is a complication of infection that leads to dangerously low blood pressure. In the UK, sepsis affects >150,000 patients annually across the age range, and death rates are
~50% in some patient groups. One of the most acute problems is an elevation of circulating adrenomedullin, a peptide hormone which causes increased permeability of blood vessels and vasodilatation leading to reduced perfusion and organ failure. Accordingly, preventing adrenomedullin promoted reduction in blood pressure is an established target for treatment in septic shock.

This project offers the opportunity to combine three powerful approaches towards the discovery of novel drug treatments for septic shock. Using a selection of small molecule building blocks, you will design novel drug targets that will be specifically tailored to bind at the key adrenomedullin receptor site. You will then synthesise these molecules and undertake an assessment of their potency through established biological assays. Specific objectives therefore are:
- To use an existing adrenomedullin receptor X-ray crystal structure together with cheminformatics methods to identify novel chemical space with potential to generate biologically-active compounds using Molecular-matched pair analysis. Machine learning will identify key features associated with bioactivity and build these features into molecular design.
- To carry out the efficient chemical synthesis of candidate compounds and to characterise their structure and purity using organic synthesis methods developed in the Lead Supervisors labs.
- To undertake biological testing of compounds generated in this project by measuring the ability of adrenomedullin to induce cAMP production in receptor expressing cells.

This project has several strands that underpin the key skills and experiences required in modern day drug discovery. Specifically, you will develop first-hand experience of in silico methods such as big data analysis & cheminformatics which will inform the small molecules that we will target. You will then develop skills as a synthetic chemist, delivering candidate compounds that you will subject to biological screening. Finally, working closely with Redbrick Molecular Ltd (a local SME) and the Medicines Discovery Catapult (Alderley Park, Cheshire), you will understand the operational requirements of large government-funded organisations as well as a small business. Overall then, this multidisciplinary project offers outstanding training across the life sciences and is ideally suited to candidates who aspire to become future leaders in the pharmaceuticals industry.

https://www.sheffield.ac.uk/chemistry/staff/profiles/joseph_harrity

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

iCASE Award: Industrial partnership project
Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck!

References

1. “A Pd-Catalyzed Annulation to Functionalized Piperidines”, B. D. W. Allen, M. J. Connolly and J.P.A. Harrity, Chem. Eur. J. 2016, 22, 13000-13003.

2. “A Sydnone Cycloaddition Route to Pyrazole-Based Analogs of Combretastatin A4”, A.W. Brown, M. Fisher, G.M. Tozer, C. Kanthou and J.P.A. Harrity, J. Med. Chem. 2016, 59, 9473-9488.

3. “Evaluation of Sydnone-Based Analogs of Combretastatin A-4 Phosphate (CA4P) as Vascular Disrupting Agents for Use in Cancer Therapy”, A.W. Brown, T. Holmes, M. Fisher, G.M. Tozer, J.P.A. Harrity and C. Kanthou ChemMedChem. 2018, 13, 2618-2626.

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