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 (ΔGbind/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 β-lactamase inhibitor suggest that this is not always the case.
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Nonadditivity in public and inhouse data: implications for drug design
Journal of Cheminformatics Open Access 02 July 2021
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This work was supported by US National Institutes of Health grant GM59957 (to B.K.S.) and Ruth L. Kirschstein National Research Service Award fellowship GM076883 (to K.B). We thank B. Feng, J. Irwin, A. Graves and Y. Chen for reading the manuscript.
The authors declare no competing financial interests.
Supplementary Fig. 1
Electron density maps of fragments (PDF 440 kb)
Supplementary Table 1
Data collection and refinement statistics (PDF 30 kb)
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Babaoglu, K., Shoichet, B. Deconstructing fragment-based inhibitor discovery. Nat Chem Biol 2, 720–723 (2006). https://doi.org/10.1038/nchembio831
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