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Science  04 Apr 2003:
Vol. 300, Issue 5616, pp. 21
DOI: 10.1126/science.300.5616.21a

Rather than trying to sample all of chemical space in searching for drug leads, designers have deconstructed the problem and compiled combinatorial libraries of fragments. This approach facilitates synthesis, especially when the target can be used as a template to favor some fragments over others. Braisted et al. have selected for weakly binding fragments by capturing them via disulfide tethering to the target. In one such instance, joining a fragment to a previously identified lead improved the inhibitory potency of an interleukin-2 antagonist by 50-fold. Erlanson et al. have extended this approach by screening for two weakly binding fragments that together conform to the linear active sites of caspases, the enzymes of apoptosis.—GJC

J. Am. Chem. Soc. 10.1021/ja034247i (2003); NatureBiotechnol.21, 308 (2003).

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