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PDBsum entry 4lh6
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Ligase/ligase inhibitor
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PDB id
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4lh6
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References listed in PDB file
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Key reference
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Title
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Identification through structure-Based methods of a bacterial NAD(+)-Dependent DNA ligase inhibitor that avoids known resistance mutations.
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Authors
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K.Murphy-Benenato,
H.Wang,
H.M.Mcguire,
H.E.Davis,
N.Gao,
D.B.Prince,
H.Jahic,
S.S.Stokes,
P.A.Boriack-Sjodin.
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Ref.
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Bioorg Med Chem Lett, 2014,
24,
360-366.
[DOI no: ]
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PubMed id
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Abstract
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In an attempt to identify novel inhibitors of NAD(+)-dependent DNA ligase (LigA)
that are not affected by a known resistance mutation in the adenosine binding
pocket, a detailed analysis of the binding sites of a variety of bacterial
ligases was performed. This analysis revealed several similarities to the
adenine binding region of kinases, which enabled a virtual screen of known
kinase inhibitors. From this screen, a thienopyridine scaffold was identified
that was shown to inhibit bacterial ligase. Further characterization through
structure and enzymology revealed the compound was not affected by a previously
disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A
subsequent medicinal chemistry program identified substitutions that resulted in
an inhibitor with moderate activity across various Gram-positive bacterial LigA
enzymes.
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