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PDBsum entry 1yy4
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Transcription
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PDB id
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1yy4
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References listed in PDB file
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Key reference
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Title
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Erbeta ligands. 3. Exploiting two binding orientations of the 2-Phenylnaphthalene scaffold to achieve erbeta selectivity.
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Authors
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R.E.Mewshaw,
R.J.Edsall,
C.Yang,
E.S.Manas,
Z.B.Xu,
R.A.Henderson,
J.C.Keith,
H.A.Harris.
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Ref.
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J Med Chem, 2005,
48,
3953-3979.
[DOI no: ]
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PubMed id
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Abstract
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The 2-phenylnaphthalene scaffold was explored as a simplified version of
genistein in order to identify ER selective ligands. With the aid of docking
studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were
predicted to be the most potentially influential positions to enhance ER
selectivity using two different binding orientations. Both orientations have the
phenol moiety mimicking the A-ring of genistein. Several compounds predicted to
adopt orientations similar to that of genistein when bound to ERbeta were
observed to have slightly higher ER affinity and selectivity than genistein. The
second orientation we exploited, which was different from that of genistein when
bound to ERbeta, resulted in the discovery of several compounds that had
superior ER selectivity and affinity versus genistein. X-ray structures of two
ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode
and suggested that substituents at positions 1 and 8 were responsible for
inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined
and found to be effective in two models of inflammation, suggesting that
targeting ER may be therapeutically useful in treating certain chronic
inflammatory diseases.
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