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PDBsum entry 3qa2
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Transferase/transferase inhibitor
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PDB id
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3qa2
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References listed in PDB file
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Key reference
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Title
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Inhibitors of ketohexokinase: discovery of pyrimidinopyrimidines with specific substitution that complements the ATP-Binding site.
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Authors
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B.E.Maryanoff,
J.C.O'Neill,
D.F.Mccomsey,
S.C.Yabut,
D.K.Luci,
A.D.Jordan,
J.A.Masucci,
W.J.Jones,
M.C.Abad,
A.C.Gibbs,
I.Petrounia.
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Ref.
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Acs Med Chem Lett, 2011,
2,
538-543.
[DOI no: ]
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PubMed id
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Abstract
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Attenuation of fructose metabolism by the inhibition of ketohexokinase (KHK;
fructokinase) should reduce body weight, free fatty acids, and triglycerides,
thereby offering a novel approach to treat diabetes and obesity in response to
modern diets. We have identified potent, selective inhibitors of human hepatic
KHK within a series of pyrimidinopyrimidines (1). For example, 8, 38, and 47
exhibited KHK IC50 values of 12, 7, and 8 nM, respectively, and also showed
potent cellular KHK inhibition (IC50 < 500 nM), which relates to their
intrinsic potency vs KHK and their ability to penetrate cells. X-ray cocrystal
structures of KHK complexes of 3, 8, and 47 revealed the important interactions
within the enzyme's adenosine 5'-triphosphate (ATP)-binding pocket.
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