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(BBSRC DTP) Developing new computer-based technologies for designing protein kinase inhibitors by quantifying peptide-protein binding.


Project Description

This PhD studentship will apply computational and mathematical techniques to one the most fundamental, important and complex of biological problems – that of protein-protein interactions. It will support the development of technologies that aim to understand and therefore allow prediction of the energies of protein-protein interaction, providing advances in our knowledge of basic molecular biological processes and enabling new routes to drug discovery. It will also provide training in computational biochemistry techniques that are urgently demanded by industry and across postdoctoral research. Post-graduates with proven biochemical/chemical and computational skills are in short supply and high demand at present and are essential to maintain the UK’s competitive position. This DTP studentship will also provide comprehensive data on the protein kinase dynamics and interactions with peptides in standard data formats, which can be read by widely available software, and hence can be readily used by others in their research projects.

Protein-protein interactions (PPIs), such as those between protein kinases and their targets, have fundamental biological importance [1], and using inhibitors to block their biological networks in a pathway-defined manner is a major pharmaceutical goal [2]. PPI interfaces are large and inhibition with small molecule is extremely difficult to achieve without off-target effects. Larger biopharmaceuticals, like peptides, are ideally suited to the specific PPI inhibition task, if methods could be developed for their targeted design. Protein kinases are extremely important drug targets and are also excellent model systems for studying PPI inhibition. Developing a strategy for blocking interactions between protein kinases and native substrates, while important in its own right, is also a significant step to finding generic approaches for specific inhibition of PPIs. The recent speedup of molecular simulations afforded by new computational architectures, the use of which we have helped pioneer [3], now permits calorimetric quantities to be calculated directly from simulations, dubbed computational calorimetry [4,5]. Compared to other computational methods for calculating binding enthalpies, computational calorimetry is advantageous in that can be used to understand the drivers of protein interaction and hence how to optimise them. Direct prediction of thermodynamic parameters for PPIs is now within reach for the first time, which can revolutionise the field by opening a route to rational peptide inhibitor design. We have already developed methods for performing computational calorimetry on protein-peptide complexes and our initial results are exciting. There now exists the opportunity to adapt these methods to the important protein kinase family and to establish a new route to PPI inhibition, a goal of significant scientific and industrial biotechnological importance. The aim of this PhD studentship, therefore, is to apply computational calorimetry to quantitatively investigate the energetics of protein kinase-peptide binding and to use these approaches to develop new methods for the design of peptide-based kinase inhibitors.

Contact for further information:

https://www.research.manchester.ac.uk/portal/andrew.almond.html
https://www.research.manchester.ac.uk/portal/a.golovanov.html

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.


References

[1]. Hayes S et al. Biochem Soc Trans 2016, 44:994-1004.
[2]. Scott DE et al. Nat Rev Drug Discov 2016, 15:533-50.
[3]. Sattelle BM et al. Journal of the American Chemical Society 2010, 132:13132-4.
[4]. Fenley AT et al. J Chem Theory Comput 2014, 10:4069-78.
[5]. Henriksen NM et al. J Chem Theory Comput 2015, 11:4377-94.

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