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PDBsum entry 4jzr
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Oxidoreductase
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PDB id
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4jzr
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References listed in PDB file
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Key reference
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Title
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Novel complex crystal structure of prolyl hydroxylase domain-Containing protein 2 (phd2): 2,8-Diazaspiro[4.5]decan-1-Ones as potent, Orally bioavailable phd2 inhibitors.
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Authors
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G.Deng,
B.Zhao,
Y.Ma,
Q.Xu,
H.Wang,
L.Yang,
Q.Zhang,
T.B.Guo,
W.Zhang,
Y.Jiao,
X.Cai,
J.Zhang,
H.Liu,
X.Guan,
H.Lu,
J.Xiang,
J.D.Elliott,
X.Lin,
F.Ren.
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Ref.
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Bioorg Med Chem Lett, 2013,
21,
6349-6358.
[DOI no: ]
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PubMed id
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Abstract
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We have discovered a novel complex crystal structure of the PHD2 enzyme with its
inhibitor, the 2,8-diazaspiro[4.5]decan-1-one analogue 4b. The widely reported
salt bridge between Arg383 of the enzyme and its inhibitors in all complex
structures published thus far was not observed in our case. In our complex
structure compound 4b forms several novel interactions with the enzyme, which
include a hydrogen bond with Arg322, a π-cation interaction with Arg322, a
π-π stacking with Trp389, and a π-π stacking with His313. Guided by the
structural information, SAR studies were performed on the
2,8-diazaspiro[4.5]decan-1-one series leading to the discovery of compound 9p
with high potency and good oral pharmacokinetic profile in mice.
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