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Research Opportunities 2010-11 Professor Colin Fishwick Professor Colin Fishwick, Professor Nigel Hooper [email protected], [email protected] Development and application of new chemical tools for site-specific chemical labelling of proteins implicated in disease This proposal is representative of the projects currently on offer in our group. For more details of our research please visit our webpages at: http://www.astbury.leeds.ac.uk/People/staffpage.php?StaffID=CWGF, and http://www.astbury.leeds.ac.uk/People/staffpage.php?StaffID=NMH. The purpose of this project is to use computational drug design, synthetic chemistry, and biological assays, to develop new photoreactive ligands for the site-specific labeling of an important protein involved in the control of LDL cholesterol. The position will suit students with a strong interest and background in synthesis who would also like to develop skills in computational molecular design and molecular and cellular biology. You will work in a vibrant, multidisciplinary research group consisting of chemists and molecular and cell biologists. The use of photoactive ligands (‘PALs’) is a powerful method for investigating the structure and function of complex biological systems and can yield precise details of the interaction of small molecule with their target proteins. Here, a functional group, which, although stable under normal conditions but transformable into a reactive intermediate with light, is placed within a known ligand (eg substrate or inhibitor) for a particular enzyme. Activation of the PAL in the presence of the target protein followed by analysis of the resulting covalently cross-linked PAL-protein conjugate yields information on the ligand binding site- Figure (a). This project will use computer-aided ligand design methods coupled to organic synthesis to produce PALs targeted to the human PCSK9 receptor which is important in the control of LDL cholesterol levels and thus, an attractive future drug target. (a) (b) Figure The project will involve the application of advanced computational techniques such as SPROUT to an X-ray crystal structure of PCSK9 (Figure (b)) in order to design tight-binding PALs. These will then be synthesised and used to probe the interaction of such molecules with PCSK9. Please contact Professor Colin Fishwick ([email protected]) for further details about this opportunity. Recent papers 1. 2. Matthew Davies, Timo Heikkilä, Glenn A. McConkey, Colin W.G. Fishwick, Mark R. Parsons and A. Peter. Johnson. Structure-Based Design, Synthesis and Characterization of Inhibitors of Human and Plasmodium falciparum Dihydroorotate Dehydrogenases. J. Med. Chem., 2009, 52, 2638 – 2693 Christopher J. Duff, Martin J,. Scott, ian T. Kirby, Sue E. Hutchinson, Steve L. Martin, and Nigel M. Hooper. Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochemical Journal, 2009, 419, 577-584 1