Health and Chemical Intervention
Researchers
- Dr Berrisford, David
- Dr Burton, Neil
- Prof Clayden, Jonathan
- Prof Flitsch, Sabine
- Dr Gardiner, John
- Prof Goodacre, Roy
- Prof Helliwell, John
- Dr Henchman, Richard
- Dr Magennis, Steven
- Dr Mair, Frank
- Prof Micklefield, Jason
- Prof Procter, David
- Dr Quayle, Peter
- Dr Ramesh, Vasudevan
- Dr Regan, Andrew
- Prof Thomas, Jim
- Dr Wallace, Timothy
- Dr Whitehead, Roger
Research Theme Leader: Professor David Procter
In the health and chemical intervention theme, researchers use chemical methods to improve the understanding of mechanism and the role of structure in biological systems. This knowledge is crucial for the design of new therapeutic agents and diagnostic tools.
Research in the theme draws heavily on our cutting-edge expertise in synthetic and biological chemistry. This expertise enables us to deliver bespoke libraries of 'engineered' small molecules, including those inspired by natural products, for use in the interrogation of biological targets. Synthetic organic chemistry groups within the theme are developing approaches to libraries of small molecules that exhibit a wide range of biological activity (e.g. anticancer, antibacterial/antibiotic, antifungal). Synthetic studies are aimed at the development of new methods for executing selective chemical changes, the construction of new heterocyclic scaffolds, the development of 'cascade reactions' for the rapid conversion of simple starting materials to bioactive products, and the honing of 'purification-lite' methods for synthesis (e.g. fluorous and solid-supported techniques).
Computational and theoretical chemistry are central in guiding our rational approaches to chemical intervention. For example, computer simulation is being used to study the hydration of proteins and their binding sites and computational methods are being applied to ligand binding and enzyme mechanism. Bioanalytical methods are being developed within the theme for quantitative proteomics and metabalomics, helping us to define targets, identify biomarkers for diagnosis, and assess potential strategies for chemical intervention. Structural chemistry teams within the theme use crystallography and NMR to elucidate structure-function relationships in important biomedical related molecular structures. In addition, fluorescence spectroscopy and imaging makes possible the study of biomolecular structure at the single-molecule level thus allowing problems in DNA replication, and DNA-metal interaction to be addressed. Teams within the theme are also designing metallo-pharmaceuticals, studying transport within artificial membranes and developing tools for drug delivery.
This highly interdisciplinary research theme benefits from extensive collaborations with academic colleagues in structural biology, biochemistry, cell biology, pharmacy and medicine. In addition, we work closely with pharmaceutical and biotech companies in drug discovery and development.
We have established the Centre for Health and Chemical Intervention in Biology and Medicine (CCIBM) in the School of Chemistry and have a Knowledge Transfer Fellow in place to conduct collaborative research, read more...
Selected publications and patents from the theme
- "Reengineering orthogonally selective riboswitches" Dixon, N.; Duncan, J. N.; Geerlings, T.; Dunstan, M. S.; McCarthy, J. E. G.; Leys, D.; Micklefield, J. Proc. Natl. Acad. Sci. USA 2010, 107, 2830. Highlighted in Nature.
- "Crystallographic Analysis of Counterion Effects on Subtilisin Enzymatic Action in Acetonitrile" Cianci, M.; Tomaszewski, B.; Helliwell, J. R.; Halling, P. J. J. Am. Chem. Soc. 2010, 132, 2293.
- "The challenge of atropisomerism in drug discovery" Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chemie Int. Ed. 2009, 48, 6398.
- "Synthesis and Biological Evaluation of Coumarin-Based Inhibitors of NAD(P)H: Quinone Oxidoreductase-1 (NQO1)" Nolan, K. A.; Doncaster, J. R.; Dunstan, M. S.; Scott, K. A.; Frenkel, A. D.; Siegel, D; Ross, D.; Barnes, J.; Levy, C.; Leys, D; Whitehead, R. C.; Stratford, I. J.; Bryce, R. A. J. Med. Chem. 2009, 52, 7142.
- "Entropic cost of protein-ligand binding and its dependence on the entropy in solution" Irudayam, S. J.; Henchman, R. H. J. Phys. Chem. B, 2009, 113, 5871.
- "Scalable synthesis of L-iduronic acid derivatives via stereocontrolled cyanohydrin reaction for synthesis of heparin-related disaccharides" Hansen, S. U.; Barath, M.; Salameh, B. A.; Pritchard, R. G.; Stimpson, W. T.; Gardiner, J. M.; Jayson, G. C. Org. Lett. 2009, 11, 4528.
- "A dialdehyde cyclization cascade in an approach to pleuromutilin" Helm, M. D.; Da Silva, M.; Sucunza, D.; Findley, T. J. K.; Procter, D. J. Angew. Chem. Int. Ed. 2009, 48, 9315.
- "Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones: selective antagonists of muscarinic (M-3) receptors" Bradshaw, B.; Evans, P.; Fletcher, J.; Lee, A. T. L.; Mwashimba, P. G.; Oehlrich, D.; Thomas, E. J.; Davies, R. H.; Allen, B. C. P.; Broadley, K. J.; Hamrouni, A; Escargueil, C. Org. Biomol. Chem. 2008, 6, 2138.
- "Carbohydrate-protein recognition probed by density functional theory and ab initio calculations including dispersive interactions" Raju, R. K.; Ramraj, A.; Vincent, M. A.; Hillier, I. H.; Burton, N. A. Phys. Chem. Chem. Phys. 2008, 10, 6500.
- "Stereoselective dearomatizing addition of nucleophiles to uncomplexed benzene rings: A route to carbocyclic sugar analogues" Clayden, J.; Parris, S.; Cabedo, N.; Payne, A H. Angew Chem. Int. Ed. 2008, 47, 5060.
- "Towards aflatoxins: a formal synthesis of aflatoxin B2" Eastham, S. A.; Ingham, S. P.; Hallett, M. R.; Herbert, J.; Modi, A.; Morley, T.; Painter, J. E.; Patel, P.; Quayle, P.; Ricketts, D. C.; Raftery, J. Tetrahedron 2008, 64, 936.
- "Chemical Compounds with a Vascular Damaging Effect" Wallace, T. W.; Edwards, D. J.; Hadfield, J. A. PCT Int. Appl. WO 2008075048, June 2008.
- "Crystal Structure of the C1 domain of Cardiac Myosin Binding Protein-C: Implications for Hypertrophic Cardiomyopathy" Govada, L.; Carpenter, L.; da Fonseca, P. C. A.; Helliwell, J. R.; Rizkallah, P. J.; Flashman, E.; Chayen, N. E.; Redwood C.; Squire J. M. J. Mol. Biol. 2008, 378, 387.
- "Microwave-Assisted Ring Opening of Epoxides: A General Route to the Synthesis of 1-Aminopropan-2-ols with Anti Malaria Parasite Activities" Robin, A.; Brown, F.; Bahamontes-Rosa, N.; Wu, B.; Beitz, E.; Kun, J. F. J.; Flitsch, S. L. J. Med. Chem. 2007, 50, 4243.
- "NMR structure of the peptidyl transferase inhibitor antibiotic amicetin" Shammas, C.; Donarski, J.; Vasudevan, R. Mag. Res. Chem. 2007, 45, 133.
- "Dual triggering of DNA binding and fluorescence via photoactivation of a dinuclear ruthenium(II) arene complex" Magennis S. W.; Habtemariam A.; Novakova O.; Henry J. B.; Meier S.; Parsons S.; Oswald I. D. H.; Brabec V.; Sadler P. J. Inorg. Chem. 2007, 46, 5059.
- "The molecular basis of the coloration mechanism in lobster shell: b-crustacyanin at 3.2 A resolution" Cianci, M.; Rizkallah, P. J.; Olczak, A.; Raftery, J.; Chayen, N. E.; Zagalsky P. F.; Helliwell J. R. Proc. Natl. Acad. Sci. USA 2002, 99, 9795.