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PDBsum entry 1l2s
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure-Based discovery of a novel, Noncovalent inhibitor of ampc beta-Lactamase.
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Authors
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R.A.Powers,
F.Morandi,
B.K.Shoichet.
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Ref.
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Structure, 2002,
10,
1013-1023.
[DOI no: ]
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PubMed id
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Abstract
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beta-lactamases are the most widespread resistance mechanisms to beta-lactam
antibiotics, and there is a pressing need for novel, non-beta-lactam drugs. A
database of over 200,000 compounds was docked to the active site of AmpC
beta-lactamase to identify potential inhibitors. Fifty-six compounds were
tested, and three had K(i) values of 650 microM or better. The best of these,
3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a competitive
noncovalent inhibitor (K(i) = 26 microM), which also reversed resistance to
beta-lactams in bacteria expressing AmpC. The structure of AmpC in complex with
this compound was determined by X-ray crystallography to 1.94 A and reveals that
the inhibitor interacts with key active-site residues in sites targeted in the
docking calculation. Indeed, the experimentally determined conformation of the
inhibitor closely resembles the prediction. The structure of the
enzyme-inhibitor complex presents an opportunity to improve binding affinity in
a novel series of inhibitors discovered by structure-based methods.
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Figure 1.
Figure 1. Comparison of the Chemical Structures of Several
b-Lactamase Ligands(A) Ampicillin, a b-lactamase substrate.(B)
Ceftazidime, a b-lactamase-resistant molecule. The R1 side chain
ubiquitous among b-lactams is labeled.(C) A boronic acid
transition-state analog inhibitor that contains the R1 side
chain from ceftazidime [9].(D) Compound 1, 3-[(4-chloroanilino)
sulfonyl]thiophene-2-carboxylic acid, a novel, competitive
inhibitor of b-lactamase.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2002,
10,
1013-1023)
copyright 2002.
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