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PDBsum entry 4hlc
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Transferase/transferase inhibitor
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PDB id
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4hlc
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References listed in PDB file
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Key reference
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Title
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Sulfonylpiperidines as novel, Antibacterial inhibitors of gram-Positive thymidylate kinase (tmk).
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Authors
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G.Martínez-Botella,
J.T.Loch,
O.M.Green,
S.P.Kawatkar,
N.B.Olivier,
P.A.Boriack-Sjodin,
T.A.Keating.
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Ref.
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Bioorg Med Chem Lett, 2013,
23,
169-173.
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PubMed id
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Abstract
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Thymidylate kinase (TMK) is an essential enzyme for DNA synthesis in bacteria,
phosphorylating deoxythymidine monophosphate (dTMP) to deoxythymidine
diphosphate (dTDP), and thus is a potential new antibacterial drug target.
Previously, we have described the first potent and selective inhibitors of
Gram-positive TMK, leading to in vivo validation of the target. Here, a
structure-guided design approach based on the initial series led to the
discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen
bonds with Arg48 in Staphylococcus aureus TMK was key to obtaining excellent
enzyme affinity, as verified by protein crystallography. Replacement of a
methylene linker in the series by a sulfonamide was accomplished with retention
of binding conformation. Further optimization of logD yielded phenol derivative
11, a potent inhibitor of TMK showing excellent MICs against a broad spectrum of
Gram-positive bacteria and >10(5) selectivity versus the human TMK homologue.
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