Dr Richard G. Doveston

Lecturer of Chemical Biology

Tel: +44 (0)116 229 7116

Email: r.g.doveston@leicester.ac.uk

Personal details

Research

My research centres on the design, synthesis and applications of bioactive small molecules. Some compounds may have direct utility in the treatment of disease and thus represent useful ‘lead compounds’ for drug discovery. Other compounds are designed as molecular tools that can be used to develop new chemical biology approaches to study disease pathways or expedite the drug discovery process.

In particular I am interested in studying protein-protein interactions (PPIs) which represent an exciting yet challenging class of drug target. With over 300,000 PPIs estimated in humans, and many shown to be implicated in disease, the discovery of small-molecule modulators of these interactions is of great interest. Whilst a vast number of de novo PPI inhibitors such as the Nutlins have been successfully developed, only a handful of complex natural product-derived PPI stabilisers such as paclitaxel (Taxol) have been exploited in the clinic (although to great effect). The number of reported synthetic stabilisers is growing, but the mode-of-action for the vast majority of these examples has been defined in a post hoc fashion. The development of rational strategies for the discovery of de novo PPI stabilisers therefore represents a significant and as yet unmet scientific challenge.

Currently, research is focussed on developing chemical biology approaches that will allow us to meet this challenge. My interests lie in molecules that act at a given PPI interface and thus (might) act like a ‘molecular glue’. Underpinned by synthetic organic chemistry, two core research avenues focus on: i) enhancing our molecular understanding of PPI stabilisation and; ii) establishing improved ligand discovery techniques.

Molecular Understanding: Better understanding of PPI stabilisation at the atomic level is essential in order to design more synthetically tractable, selective and potent small molecules. To achieve this a combination of in silico evaluation, synthesis, biophysical and structural evaluation is being used to enhance our understanding of natural product PPI stabilisers. As a case in point, the mechanism for fusicoccin A stabilisation of 14-3-3 protein interaction with p53 is not well understood.

Figure showing a crystal structure of Fusicoccin A stabilising the interaction of 14-3-3 protein with the C-terminal domain of p53. The precise molecular mechanism for stabilisation is not well understood.

Ligand Discovery: The development of assay technologies geared toward the identification of small molecule PPI stabilisers is essential for driving drug discovery. An approach that is currently under investigation seeks to harness the complexity of protein-drug-protein ternary complexes through protein-templated synthesis.

 

An extension of this work will be to better understand and evaluate small molecule PPI stabilisation in a cellular context. Thus, the development of disease-relevant cell-based assays through collaborative efforts is a major goal.

Selected Publications

Small-Molecule Stabilization of the p53 – 14-3-3 Protein-Protein Interaction, R. G. Doveston, A. Kuusk, S. A. Andrei, S. Leysen, Q. Cao, M. P. Castaldi, A. Hendricks, L. Brunsveld, H. Chen, H. Boyd, C. Ottmann, FEBS Letts., 2017, 591, 2449-2457.

Structural Interface Between LRRK2 and 14-3-3 Protein, L. M. Stevers, R. M. J. de Vries, R. G. Doveston, L.-G. Milroy, L. Brunsveld, C. Ottmann, Biochem. J., 2017, 474, 1273-1287.

Synthesis and Demonstration of the Biological Relevance of sp(3)-rich Scaffolds Distantly Related to Natural Product Frameworks, D. J. Foley, P. G. E. Craven, P. M. Collins, R. G. Doveston, A. Aimon, R. Talon, I. Churcher, F. von Delft, S. P. Marsden, A. Nelson, Chem. Eur. J., 2017, 23, 15227-15232.

Modulators of 14-3-3 Protein-Protein Interactions, L. M. Stevers, E. Sijbesma, M. Botta, C. MacKintosh, T. Obsil, I. Landrieu, Y. Cau, A. J. Wilson, A. Karawajczyk, J. Eickhoff, J. Davis, M. M. Hann, G. O’Mahony, R. G. Doveston, L. Brunsveld, C. Ottmann, J. Med. Chem., 2017, DOI: 10.1021/acs.jmedchem.7b00574

Stabilization of Protein-Protein Interactions in Drug Discovery, S. A. Andrei, E. Sijbesma, M. Hann, J. Davis, G. O'Mahony, M. W. D. Perry, A. Karawajczyk, J. Eickhoff, L. Brunsveld, R. G. Doveston, L-G. Milroy, C. Ottmann, Exp. Op. Drug Discov., 2017, 12, 925-940.

A Divergent Synthetic Approach to Diverse Molecular Scaffolds: Assessment of Lead-Likeness Using LLAMA, an Open-Access Computational Tool, I. Colomer, C. J. Empson, P. G. E. Craven, Z. Owen, R. G. Doveston, I. Churcher, S. P. Marsden, A. Nelson, Chem. Comm, 2016, 52, 7209-7212.

A Systematic Approach to Diverse, Lead-Like Scaffolds from α,α -Disubstituted Amino Acids, D. J. Foley, R. G. Doveston, I. Churcher, A. Nelson, S. P. Marsden, Chem. Comm., 2015, 51, 11174-11177.

A Unified Lead-Oriented Synthesis of Over Fifty Molecular Scaffolds, R. G. Doveston, P. Tosatti, M. Dow, D. J. Foley, H. Y. Li, A. J. Campbell, D. House, I. Churcher, S. P. Marsden, A. Nelson, Org. Biomol. Chem., 2015, 13, 859-865.

Towards the Realisation of Lead-Oriented Synthesis, R. G. Doveston, S. P. Marsden, A. Nelson, Drug Discov. Today, 2014, 19, 813-819.

Share this page:

Contact Details

Department of Chemistry
University of Leicester
Leicester, LE1 7RH, UK

Email: chemistry@le.ac.uk

Tel: [+44] (0)116 252 2100

Fax: [+44] (0)116 252 3789

RSS Logo Subscribe to our news

Facebook logo Like us on Facebook

Twitter @leicesterchemistry Follow us on Twitter

Just click on the logos to keep up to date with our activities!

Department Video

Athena Swan

AS Silver

DisabledGo

DisabledGo logo

The University of Leicester is committed to equal access to our facilities. DisabledGo has a detailed accessibility guide for the George Porter Building.