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Designing phosphatase inhibitors using novel quantum mechanical calculations.

Faculty of Biology, Medicine and Health

About the Project

Phosphatases play important regulatory roles in biochemical pathways that have been linked to a range of human diseases, including: cancer, diabetes and infection. These enzymes have been the subject of many drug discovery efforts that have failed and this has led to many viewing them as being undruggable. Dr Leach has recently developed new computational methods that are remarkably accurate for predicting the strength of binding interactions between proteins and other molecules. By employing quantum mechanics, these methods are amenable to both covalent and non-covalent modes of interaction. In this project, the student will apply these computational methods to a range of phosphatases of current interest with the aim of designing new classes of inhibitors that could use either of these types of interaction. Optionally, the student could then prepare compounds and test their predictions.

In detail, the first part of the project will see the student gathering datasets relating to binding strength between small molecules and phosphatase enzymes. Those under study at that point in time (in Dr Tabernero’s laboratory) will be prioritised and are likely to be linked to cancer or infectious disease. The student will then prepare protein structures for the calculations; if a protein structure is available, this will be used but if not, homology modelling and dynamics simulation will be used to generate the structure. Quantum mechanical calculations will be performed using ligands with known binding energies. Once successful correlations of computed and measured binding energies are achieved, this model system will then be used to design new inhibitors. This will include non-covalent and covalent inhibitors and will also allow the student to perform detailed calculations of the mechanism of action of the enzyme in order to understand how the catalytic machinery of the enzyme can facilitate covalent reactivity of a range of covalent inhibitors.

Candidates are expected to hold (or be about to obtain) a minimum 2.1 (or equivalent) in a related area / subject. Candidates with an interest in computational chemistry or biology are encouraged to apply.

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website ( Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Bioinformatics.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit

Funding Notes

Applications are invited from self-funded students. This project has a Band 1 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy 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.


"Predicting protein–ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A” Lukac, I.; Abdelhakim, H.; Ward, R. A.; St-Gallay, S. A.; Madden, J. C.; Leach, A. G.* Chem. Sci. 2019, 10, 2218-2227.

“A monomeric form of iNOS can rationalise observed SAR for inhibitors of dimerisation: quantum mechanics and docking compared” Leach, A. G.*; Olsson, L.-L.; Warner, D. J. Med. Chem. Comm. 2013, 4, 180-186

“Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling” Hunter, T. Cell, 1995, 80, 225-236.

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