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  (MRC DTP CASE) Prediction of substrate binding geometry and strength in promiscuous enzymes: computational chemistry applicable to the design of pharmaceuticals and agrochemicals

   Faculty of Biology, Medicine and Health

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  Dr Andrew Leach, Dr S De Visser, Dr Cristina Trujillo  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

We are often taught about the power of enzymes to select particular substrates from the biological milieu and of their ability to perform highly selective reactions on those substrates. Enzymes that are unselective are therefore a surprise and yet a number of processes in the metabolism of animals and plants rely upon enzymes that process a broad repertoire of substrates. Notable examples include 1) the subset of cytochromes P450 that are responsible for metabolising many drugs and 2) the glutathione-S-transferases that conjugate a range of electrophilic compounds with glutathione thereby removing reactive species from the organism. In performing these reactions, both of these classes of enzyme can also remove drugs or agrochemicals preventing them having their desired activity.

In this project, you will apply the theoceptor (theoretical receptor) computational method that has been developed in the Leach group to these two groups of enzymes. This quantum mechanical method provides an accurate ability to predict the geometry and energy of drug-like molecules binding to proteins. Its ability to perform the same feat for enzyme-substrate complexes has not yet been tested and you will undertake this research. The Leach group has collated a large set of biochemical parameters (such as K and k­cat) for the cytochromes P450 and you will begin with these systems. An interesting aspect of these enzymes is that their binding site contains a heme co-factor. Although much computational work (including by Manchester researchers) has gone into investigating the reaction mechanism of these enzymes, the factors that govern the initial (reversible) substrate binding have not been probed in the same detail. You will combine quantum mechanical and logP calculations to build models for binding energy and impute the binding geometries. Subsequently, you will extend your studies to the glutathione S-transferases where the challenge of modelling the placement of both the electrophile and the glutathione and understanding the importance of both in the initial substrate complex must be tackled. Working with colleagues involved in developing the RetroBioCat system that helps chemists incorporate biological catalysts into their route planning will provide an opportunity for you to apply the methods developed to enhance this valuable tool.

You will join a friendly group, based in the division of pharmacy and optometry, that will provide you with many opportunities to work with a wide range of scientists. You will undertake a placement with Medchemica where you will experience industrially relevant drug design.


Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC DTP website

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website

Biological Sciences (4) Chemistry (6) Computer Science (8) Medicine (26)

Funding Notes

This is a 4 year CASE studentship in partnership with Medchemica Limited. This scheme is open to UK applicants only. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.


“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.
“Mapping Ligand Shape Space for Protein-Ligand Systems; Distinguishing Key-in-Lock and Hand-in-Glove Proteins”
Zarnecka, J.; Lukac, I.; Messham, S. J.; Hussin, A.; Coppola, F.; Enoch, S. J.; Dossetter, A. G.; Griffen, E. J.; Leach, A. G.* J. Chem. Inf. Model. 2021, 61, 1859-1874.
“Tuning The Binding Affinity And Selectivity Of Perfluoroaryl‐Stapled Peptides By Cysteine‐Editing”
Verhoork, S. M.; Jennings, C. E; Rozatian, N.; Reeks, J.; Meng, J.; Corlett, E. K.; Bunglawala, F.; Noble, M. E. M.; Leach, A. G; Coxon, C. R. Chem. Eur. J. 2019, 25, 177-182.
“Design, Synthesis and Evaluation of Tryptophan Analogues as Tool Compounds to Study IDO1 Activity”
Cundy, N. J.; Hare R. K.; Tang, T.; Leach, A. G.; Jowitt, T. A.; Qureshi, O.; Gordon, J.; Barnes, N. M.; Brady, C. A.; Raven, E. L.; Grainger, R. S.; Butterworth, S. RSC Chem. Biol. 2021, 2, 1651-1660.
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