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PDBsum entry 6ms7
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Transcription
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PDB id
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6ms7
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References listed in PDB file
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Key reference
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Title
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Identification and structural insight of an effective pparγ modulator with improved therapeutic index for anti-Diabetic drug discovery.
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Authors
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H.Jiang,
X.E.Zhou,
J.Shi,
Z.Zhou,
G.Zhao,
X.Zhang,
Y.Sun,
K.Suino-Powell,
L.Ma,
H.Gao,
X.Yu,
J.Li,
J.Li,
K.Melcher,
H.E.Xu,
W.Yi.
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Ref.
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Chem Sci, 2020,
11,
2260-2268.
[DOI no: ]
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PubMed id
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Abstract
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Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of
glucose homeostasis and lipid metabolism, and an important target for the
development of modern anti-diabetic drugs. However, current PPARγ-targeting
anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated
with undesirable side effects. To address this concern, we here describe the
structure-based design, synthesis, identification and detailed in vitro
and in vivo characterization of a novel, decanoic acid (DA)-based and
selective PPARγ modulator (SPPARγM), VSP-77, especially (S)-VSP-77, as the
potential "hit" for the development of improved and safer
anti-diabetic therapeutics. We have also determined the co-crystal structure of
the PPARγ ligand-binding domain (LBD) in complex with two molecules of
(S)-VSP-77, which reveal a previously undisclosed allosteric binding mode.
Overall, these findings not only demonstrate the therapeutic advantage of
(S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but
also provide a rational basis for the development of future SPPARγMs as safe
and highly efficacious anti-diabetic drugs.
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