Letter abstract
Nature Chemical Biology 2, 720 - 723 (2006)
Published online: 29 October 2006 | doi:10.1038/nchembio831
Deconstructing fragment-based inhibitor discovery
Kerim Babaoglu1 & Brian K Shoichet1
Fragment-based screens test multiple low–molecular weight molecules for binding to a target1, 2, 3, 4. Fragments often bind with low affinities but typically have better ligand efficiencies (
Gbind/heavy atom count) than traditional screening hits5. This efficiency, combined with accompanying atomic-resolution structures, has made fragments popular starting points for drug discovery programs2, 6, 7, 8, 9, 10, 11, 12, 13. Fragment-based design adopts a constructive strategy: affinity is enhanced either by cycles of functional-group addition or by joining two independent fragments together. The final inhibitor is expected to adopt the same geometry as the original fragment hit. Here we consider whether the inverse, deconstructive logic also applies—can one always parse a higher-affinity inhibitor into fragments that recapitulate the binding geometry of the larger molecule? Cocrystal structures of fragments deconstructed from a known 
-lactamase inhibitor suggest that this is not always the case.
- Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th St., MC 2550, San Francisco, California 94158-2330, USA.
Correspondence to: Brian K Shoichet1 e-mail: shoichet@cgl.ucsf.edu
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