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PDBsum entry 5etl
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Transferase/transferase inhibitor
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PDB id
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5etl
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References listed in PDB file
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Key reference
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Title
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Structural basis for the selective binding of inhibitors to 6-Hydroxymethyl-7,8-Dihydropterin pyrophosphokinase from staphylococcus aureus and escherichia coli.
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Authors
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M.L.Dennis,
N.P.Pitcher,
M.D.Lee,
A.J.Debono,
Z.C.Wang,
J.R.Harjani,
R.Rahmani,
B.Cleary,
T.S.Peat,
J.B.Baell,
J.D.Swarbrick.
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Ref.
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J Med Chem, 2016,
59,
5248-5263.
[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 a member of the
folate biosynthesis pathway found in prokaryotes and lower eukaryotes that
catalyzes the pyrophosphoryl transfer from the ATP cofactor to a
6-hydroxymethyl-7,8-dihydropterin substrate. We report the chemical synthesis of
a series of S-functionalized 8-mercaptoguanine (8MG) analogues as substrate site
inhibitors of HPPK and quantify binding against the E. coli and S. aureus
enzymes (EcHPPK and SaHPPK). The results demonstrate that analogues
incorporating acetophenone-based substituents have comparable affinities for
both enzymes. Preferential binding of benzyl-substituted 8MG derivatives to
SaHPPK was reconciled when a cryptic pocket unique to SaHPPK was revealed by
X-ray crystallography. Differential chemical shift perturbation analysis
confirmed this to be a common mode of binding for this series to SaHPPK. One
compound (41) displayed binding affinities of 120 nM and 1.76 μM for SaHPPK and
EcHPPK, respectively, and represents a lead for the development of more potent
and selective inhibitors of SaHPPK.
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