PhD Studentship: Molecular Simulation Approaches to Scaffold-Hopping

Supervisory Team: J.W. Essex and J.G. Frey

PhD Supervisor: Jon Essex

Project description:

The search for drug molecules is risky and expensive. Having identified a high quality and tractable chemical starting point (a hit), further optimisation takes place by modifying the functional groups attached to a central, rigid-ring scaffold. This central scaffold is seldom changed, as optimising new chemistry without a clear view on whether the molecule is effective, is time consuming and expensive. Reliable in-silico predictions of binding affinity for new scaffolds (without wet-lab work) would be a game-changing tool.

Free energy calculations using molecular dynamics are widely used in the pharmaceutical industry to predict drug binding affinities. Scaffold hopping presents distinct challenges however. The very large number of possible alternate scaffolds means that the method used must be very efficient, while the potentially large chemical change creates problems with method accuracy. In this project you will address these problems.

Here you will enumerate possible alternate scaffold structures for a known hit molecule. You will use advanced free energy simulations to target these scaffolds quickly, and optimise the binding affinity estimates by incorporating quantum mechanical energies. Finally, the synthetic accessibility of the candidate scaffolds will be assessed to provide a ranked list for synthesis and testing.

You will spend at least 3 months of this 3 ½ year studentship working at Kvantify, where you will learn how computer modelling is applied to drug discovery. You will be supervised by Prof Jonathan Essex at the University of Southampton, and by Dr Michael Carter from Kvantify. Both are expert in the development and application of computational methods to drug discovery.

If you wish to discuss any details of the project informally, please contact Jonathan Essex, Email: jwe1@soton.ac.uk

Entry Requirements

You will have a first or upper second class degree (or its international equivalent) in Chemistry, Biochemistry, Physics, Engineering or Computer Science. You will have a keen interest in working outside a single discipline, possess good communication and organisational skills, and be highly self-motivated and proactive. This studentship is open to both UK and EU citizens.

Closing date: 31 August 2024.

Applications will be considered in the order that they are received, the position will be considered filled when a suitable candidate has been identified.

Funding: We offer a range of funding opportunities for both UK and international students, including Bursaries and Scholarships.  For more information please visit PhD Scholarships | Doctoral College | University of Southampton  Funding will be awarded on a rolling basis, so apply early for the best opportunity to be considered.

How To Apply

Apply online: HERE Select programme type (Research), 2024/25, Faculty of Engineering and Physical Sciences, next page select “PhD Chemistry (Full time)”. In Section 2 of the application form you should insert the name of the supervisor J.W. Essex

Applications should include:

Curriculum Vitae

Two reference letters

Degree Transcripts/Certificates to date

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