2hdu
AmpC beta-lactamase in complex with 2-acetamidothiophene-3-carboxylic acid
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OverviewOverview
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.
About this StructureAbout this Structure
2HDU is a Single protein structure of sequence from Escherichia coli with K, PO4 and F12 as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
ReferenceReference
Deconstructing fragment-based inhibitor discovery., Babaoglu K, Shoichet BK, Nat Chem Biol. 2006 Dec;2(12):720-3. Epub 2006 Oct 29. PMID:17072304
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