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PDBsum entry 2hdr
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References listed in PDB file
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Key reference
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Title
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Deconstructing fragment-Based inhibitor discovery.
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Authors
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K.Babaoglu,
B.K.Shoichet.
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Ref.
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Nat Chem Biol, 2006,
2,
720-723.
[DOI no: ]
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PubMed id
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Abstract
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Fragment-based screens test multiple low-molecular weight molecules for binding
to a target. Fragments often bind with low affinities but typically have better
ligand efficiencies (DeltaG(bind)/heavy atom count) than traditional screening
hits. This efficiency, combined with accompanying atomic-resolution structures,
has made fragments popular starting points for drug discovery programs.
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
beta-lactamase inhibitor suggest that this is not always the case.
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Figure 3.
Interacting side chains and active site Ser64 are shown as
sticks to orient the viewer. The unbiased F[o] – F[c] electron
density is also shown, contoured at 3  .
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Figure 4.
Shown is crystal structure of fragment F4 (purple carbons)
overlaid on that of the lead L1 (white carbons).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Chem Biol
(2006,
2,
720-723)
copyright 2006.
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