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PDBsum entry 4hyp
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Isomerase/isomerase inhibitor
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PDB id
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4hyp
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References listed in PDB file
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Key reference
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Title
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Pyrrolopyrimidine inhibitors of DNA gyrase b (gyrb) and topoisomerase IV (pare). Part i: structure guided discovery and optimization of dual targeting agents with potent, Broad-Spectrum enzymatic activity.
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Authors
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L.W.Tari,
M.Trzoss,
D.C.Bensen,
X.Li,
Z.Chen,
T.Lam,
J.Zhang,
C.J.Creighton,
M.L.Cunningham,
B.Kwan,
M.Stidham,
K.J.Shaw,
F.C.Lightstone,
S.E.Wong,
T.B.Nguyen,
J.Nix,
J.Finn.
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Ref.
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Bioorg Med Chem Lett, 2013,
23,
1529-1536.
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PubMed id
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Abstract
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The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are
essential enzymes that control the topological state of DNA during replication.
The high degree of conservation in the ATP-binding pockets of these enzymes make
them appealing targets for broad-spectrum inhibitor development. A
pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment
screen with optimization potential. Structural characterization of inhibitor
complexes conducted using selected GyrB/ParE orthologs aided in the
identification of important steric, dynamic and compositional differences in the
ATP-binding pockets of the targets, enabling the design of highly potent
pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting
activity.
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