Centre for Computational Drug Discovery

Professor Christopher A. REYNOLDS

Department of Biological Sciences

University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK

Tel: +44 1206 872540 Fax: +44 1206 872592

e-mail: C.A.Reynolds@essex.ac.uk

Find out more information by visiting his web site http://www.essex.ac.uk/bs/staff/reync/

Research Interests

The research group's expertise is in the development of methods in computational chemistry and their application to problems in chemistry and biology. Recent methodology developments have been in the areas of bioinformatics, electrostatics and hybrid QM/MM methods, with a particular focus on dimerization as an important event in signal transduction.. Recent applications involve studies on transition metal based anti-cancer drugs, G-protein coupled receptors and MHC class II receptors,

Hypoxia-selective agents. Hypoxia may severely limit the curability of tumours, particularly solid tumours. However, this lack of oxygen is a key differences between cancer cells and normal cells that can be exploited. We are particularly interested in transition metal-based hypoxia-selective agents, and this work in particular has benefited from the recent developments in density functional theory. For example, the LUMO of the Co(III) lead bioreductive agent [Co(Meacac)₂dce]⁺ shown left may be used to design more stable analogues. Our current focus is on copper-based rather than cobalt-based agents because of their potential use in imaging and therapy.

Dimerization and signal transduction. Cancer may arise as a result of failures in signal transduction within a cell. Dimerisation is a key event in many of these signal transduction events, e.g. tyrosine kinase receptors, helix-loop-helix transcription regulators and G-protein coupled receptors (GPCRs). Our bioinformatics and modelling approaches to studying receptor dimerization have been developed largely on the GPCR systems. Key regions of the prostanoid dimerization interface, as shown using the evolutionary trace and entropy-based methods are shown right. These methods and are now being applied to systems with a higher profile in the development of cancer, with a view to developing strategies to inhibit dimerization and hence aberrant signalling.

Recent publications

Blower PJ, Dilworth JR, Maurer RI, Mullen GD, Reynolds CA, Zheng Y., Towards new transition metal-based hypoxic selective agents for therapy and imaging, J Inorg Biochem 2001, 85(1):15-22. (pubmed abstract)
C. Higgs, C.A. Reynolds, Modelling G-protein coupled receptors, in Theoretical Biochemistry - Processes and Properties of Biological Systems, vol 9 in series Theoretical and Computational Chemistry, Ed L.A. Eriksson, Elsevier, Amsterdam, 2001, pp341-376.
P.R. Gouldson, M.K. Dean, C.R. Snell, R.P. Bywater, G. Gkoutos, C.A. Reynolds, Lipid facing correlated mutations and dimerization in G-protein coupled receptors, Prot. Engineering, 2001, 14, in press
P.R. Gouldson, R.E. Smith, M.K. Dean, C. Higgs, G.V. Gkoutos, C.A. Reynolds, Dimerisation and Domain swapping in GPCRs: a computational approach, Neuropsychopharmacology, (2000) 23, S61-S77. (pubmed abstract)
J.H. Wu, C.A. Reynolds, Cyclophosphamides as hypoxia-activated diffusible cytotoxins: a theoretical study, J Comput Aided Mol Des. 14, (2000) 307-16. (pubmed abstract)
Gooding SR, Winn PJ, Maurer RI, Ferenczy GG, Miller JR, Harris JE, Griffiths DV, Reynolds CA, Fully polarizable QM/MM calculations: An application to the nonbonded iodine-oxygen interaction in dimethyl-2-iodobenzoylphosphonate, J. Comput. Chem., 21, (2000) 478-482.
R.I. Maurer, Christopher A Reynolds, Modelling Biological Systems, Royal Society of Chemistry Specialist Periodical Report on Molecular Modelling, Ed.A. Hinchliffe., 2000, in press.
J.H.Wu, P.J. Winn, G.G.Ferenczy and C.A. Reynolds, Solute polarization and the design of cobalt complexes as redox active therapeutic agents, Int. J. Quant. Chem. Biophys. Quarterly 73, (1999) 229-236.
A. Nilsson, M. Wijayawardene, G. Gkoutos, K.M. Wilson, N. Fernandez and C.A. Reynolds, Correlated mutations in the HLA class II molecule, Int. J. Quant. Chem. Biophy. Quarterly, 73, (1999) 85-96.