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Upon completion of his doctorate in synthetic organic chemistry at the University of Liverpool in 1985, Dr. Colin W.G. Fishwick joined the faculty at University of Leeds, School of Chemistry where he is currently Reader in Organic Chemistry. His research is focused on a number of areas including the development of new synthetic reactions with particular emphasis, in recent years, on the synthesis of biologically active molecules and on the study and application of molecular self-assembly. Additionally, in recent years, he has published key findings on the application of computer-aided molecular design to the production of sub micromolar inhibitors of bacterial and malarial enzymes and human receptors respectively. In collaboration with various groups both nationally and internationally, he is presently using computational and synthetic techniques to produce small-molecule inhibitors for use in the treatment of both infective- and non-infective diseases, respectively. Within the infective diseases area, systems presently under study include a range of enzymes derived from pathogens including those involved in bacterial cell-wall biosynthesis, and in the biosynthesis of nucleic acids from malarial parasites. Research on the production of inhibitors of enzymes associated with non-infective diseases includes work on the development of new anti thrombotics, and new anticancer compounds.
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De Novo Molecular Design and vHTS: a Powerful Strategy for Drug Discovery
Colin W.G.Fishwick, University of Leeds, School of Chemistry
In silico molecular docking techniques, such as virtual high-throughput screening (VHTS), are powerful approaches to the discovery of new enzyme inhibitors. Additionally, de novo design is a powerful complementary strategy for inhibitor discovery. Here, by using the structural features present within the enzyme only, new inhibitor designs are built-up sequentially according to the requirements of the targeted binding site. Therefore, de novo design is an important technique to use in parallel with VHTS in a particular hit identification campaign, as a good de novo design program will examine structure space larger by many orders of magnitude than that of most virtual libraries currently used for this purpose. We have recently applied both the de novo molecular design computer program SPROUT, and the VHTS program eHiTS to a number of therapeutically attractive enzyme targets and have, in the majority of cases under study, rapidly identified inhibitors in the micromolar range or better.
References
G.E. Besong, J.M Bostock, W. Stubbings, I. Chopra, A.P. Johnson, D.I. Roper, A.J. Lloyd, and C.W.G. Fishwick. A novel de novo designed inhibitor of D-ala-D-ala ligase from E.coli. Angew. Chem. Int. Ed. Engl., 2005, 44, 6403 - 6.
M.A. Ali, N. Bhogal, J.B.C. Findlay, and C.W.G. Fishwick. The first de novo designed antagonists of the human NK2 receptor. J. Med. Chem, 48, 2005, 5655-58
T. Heikkila, S. Thrumalairajan, M. Davies, A.P. Johnson, G. McConkey, and C.W.G. Fishwick. The first de novo designed inhibitors of plasmodium falciparum dihydroorotate dehydrogenase. Bioorg. Med. Chem. Lett., 2006, 16, 88-92
C. Ramsey, C. Galtier, A.M.W. Stead, A.P. Johnson, T. Heikilla, M. Davies, C.W.G. Fishwick, A.N. Boa, and G. McConkey. J. Med. Chem., 2007, 50, 186 – 191.
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