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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
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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
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