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PDBsum entry 4m5h
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Transferase/transferase inhibitor
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PDB id
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4m5h
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References listed in PDB file
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Key reference
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Title
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The identification, Analysis and structure-Based development of novel inhibitors of 6-Hydroxymethyl-7,8-Dihydropterin pyrophosphokinase.
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Authors
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M.K.Yun,
D.Hoagland,
G.Kumar,
M.B.Waddell,
C.O.Rock,
R.E.Lee,
S.W.White.
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Ref.
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Bioorg Med Chem Lett, 2014,
22,
2157-2165.
[DOI no: ]
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PubMed id
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Abstract
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6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an essential
enzyme in the microbial folate biosynthetic pathway. This pathway has proven to
be an excellent target for antimicrobial development, but widespread resistance
to common therapeutics including the sulfa drugs has stimulated interest in HPPK
as an alternative target in the pathway. A screen of a pterin-biased compound
set identified several HPPK inhibitors that contain an aryl substituted
8-thioguanine scaffold, and structural analyses showed that these compounds
engage the HPPK pterin-binding pocket and an induced cryptic pocket. A
preliminary structure activity relationship profile was developed from
biophysical and biochemical characterizations of derivative molecules. Also, a
similarity search identified additional scaffolds that bind more tightly within
the HPPK pterin pocket. These inhibitory scaffolds have the potential for rapid
elaboration into novel lead antimicrobial agents.
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