1xqc
From Proteopedia
(New page: 200px<br /> <applet load="1xqc" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xqc, resolution 2.05Å" /> '''X-ray structure of ...) |
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| - | [[Image:1xqc.gif|left|200px]]<br /> | + | [[Image:1xqc.gif|left|200px]]<br /><applet load="1xqc" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1xqc" size=" | + | |
caption="1xqc, resolution 2.05Å" /> | caption="1xqc, resolution 2.05Å" /> | ||
'''X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution'''<br /> | '''X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution'''<br /> | ||
==Overview== | ==Overview== | ||
| - | We disclose herein the discovery of estrogen receptor alpha (ERalpha) | + | We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XQC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with AEJ as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1XQC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=AEJ:'>AEJ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XQC OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bischoff, S | + | [[Category: Bischoff, S F.]] |
[[Category: Buhl, T.]] | [[Category: Buhl, T.]] | ||
[[Category: Floersheim, P.]] | [[Category: Floersheim, P.]] | ||
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[[Category: Halleux, C.]] | [[Category: Halleux, C.]] | ||
[[Category: Kallen, J.]] | [[Category: Kallen, J.]] | ||
| - | [[Category: Keller, H | + | [[Category: Keller, H J.]] |
[[Category: Ramage, P.]] | [[Category: Ramage, P.]] | ||
[[Category: Renaud, J.]] | [[Category: Renaud, J.]] | ||
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[[Category: nuclear hormone receptor]] | [[Category: nuclear hormone receptor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:57:31 2008'' |
Revision as of 13:57, 21 February 2008
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X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution
Contents |
Overview
We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
Disease
Known diseases associated with this structure: Atherosclerosis, susceptibility to OMIM:[133430], Breast cancer OMIM:[133430], Estrogen resistance OMIM:[133430], HDL response to hormone replacement, augmented OMIM:[133430], Migraine, susceptibility to OMIM:[133430], Myocardial infarction, susceptibility to OMIM:[133430]
About this Structure
1XQC is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands., Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P, J Med Chem. 2005 Jan 27;48(2):364-79. PMID:15658851
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