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Structure-based drug discovery. Structural biology of wild-type & mutant fibroblast growth factor receptors


Drug discovery in the pharmaceutical industry is increasingly dependent on knowledge of the three-dimensional structures of macromolecular targets. On some occasions the three-dimensional structure of a target protein may be available from Xray analysis or NMR structure determination However, drug targets are usually first identified in terms of their sequence, often through the increasing efforts in human genome sequencing in academia and industry. For the period when only the sequence of the target is available, methods of comparative modelling are of major importance. Many groups have developed algorithms for comparative modelling which depends on knowledge of the three-dimensional structure of a homologue, or even a distantly related member of a protein superfamily. Examples of this at Birkbeck include the development of
anti-hypertensives through the design of inhibitors of human renin; the human renin model was constructed in 1983 (Blundell et al. 1983 Nature 304: 273-275) and used in the pharmaceutical industry for eight or nine years before the X-ray structure was determined (Dhanaraj, Blundell et al. 1992 Nature 357: 466-472). A further example is HIV proteinase which was modelled on a more distant superfamily relationship and used in drug discovery before its structure was determined in the Wlodawer laboratory in the US and in the Blundell laboratory at Birkbeck several years later in 1989.
The research programme will begin by using modelling software developed at Birkbeck in Professor Blundell's group, including COMPOSER (Sutcliffe et al 1987 Protein Engineering 1:377-384) and MODELLER (Sail & Blundell 1993 Journal of Molecular Biology 243: 779-815). We will then extend their application to modelling inhibitors and substrate, by developing a framework of the inhibitor bound to a related protein.
Specific areas of interest will be peptide hormone interactions with receptors and the design of peptido-mimetics. We shall focus on either NGF receptor or FGF receptor interactions, both of which have been experimentally studied in the UK.

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