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| Tom Blundell - | |
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Tom L. Blundell,
Department of Biochemistry, University of Cambridge, Tennis Court
Road, Cambridge CB2 1GA
Knowledge of the three-dimensional structures of protein targets now
emerging from genomic data has the potential to accelerate greatly
drug discovery, but technical challenges and time constraints have
traditionally limited their use primarily to lead optimization. Their
application is now being extended beyond structure determination,
into new approaches for lead discovery (for review see Blundell et
al., 2002). Virtual screening coupled with high throughput X-ray
crystallography is focused on identifying one or more weakly binding
small-molecule fragments from compound libraries consisting of
hundreds of small-molecule fragments. The high-resolution definition
of this binding interaction provides an information-rich starting
point for medicinal chemistry. The use of high throughput X-ray
crystallography does not end there, as it becomes a rapid technique
to guide the elaboration of the fragments into larger molecular
weight lead compounds.
One major challenge for drug discovery arises from the very large
surfaces that are characteristic of many of the protein complexes,
for example those involved in receptor recognition and signal
transduction (see for example, Pellegrini et al., 2000). Not only
is it difficult to bind a small molecule to the large, relatively
flat surfaces of many proteins involved in protein interactions,
it would also be difficult to disrupt the interaction entirely even
if one did. It remains to be seen whether the emerging lead
discovery approaches discussed in this lecture will prove suitable
for these systems. However, a recent analysis of one multiprotein
system involving the human recombinase, Rad51, and the product of
the breast cancer associated gene, BRCA2, gene is not only
scientifically revealing but offers an encouraging and perhaps
more druggable site of interaction, and could be used to target
agents that would be helpful during chemo- or radio-therapy..
1. Blundell, T.L., Jhoti, H. and Abell, C. (2002).Nature Reviews
Drug Discovery. 1, 45-54;
2. Pellegrini L., Burke D.F., von Delft F., Mulloy B., Blundell
TL (2000) Nature 407, 1029-1034
3. Pellegrini L, Yu DS, Lo T, Anand S, Lee M, Blundell TL,
Venkitaraman AR (2002) Nature 420, 287-293
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