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3gmd

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==Structure-based design of 7-Azaindole-pyrrolidines as inhibitors of 11beta-Hydroxysteroid-Dehydrogenase type I==
==Structure-based design of 7-Azaindole-pyrrolidines as inhibitors of 11beta-Hydroxysteroid-Dehydrogenase type I==
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<StructureSection load='3gmd' size='340' side='right' caption='[[3gmd]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
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<StructureSection load='3gmd' size='340' side='right'caption='[[3gmd]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3gmd]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GMD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3GMD FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3gmd]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GMD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GMD FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2M3:2-METHYL-3-{(3S)-1-[(1-PYRIDIN-2-YLCYCLOPROPYL)CARBONYL]PYRROLIDIN-3-YL}-1H-PYRROLO[2,3-B]PYRIDINE'>2M3</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.28&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Hsd11, Hsd11b1, HSD11L ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2M3:2-METHYL-3-{(3S)-1-[(1-PYRIDIN-2-YLCYCLOPROPYL)CARBONYL]PYRROLIDIN-3-YL}-1H-PYRROLO[2,3-B]PYRIDINE'>2M3</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/11-beta-hydroxysteroid_dehydrogenase 11-beta-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.146 1.1.1.146] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3gmd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gmd OCA], [https://pdbe.org/3gmd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gmd RCSB], [https://www.ebi.ac.uk/pdbsum/3gmd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gmd ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3gmd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gmd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3gmd RCSB], [http://www.ebi.ac.uk/pdbsum/3gmd PDBsum]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/DHI1_MOUSE DHI1_MOUSE]] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.
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[https://www.uniprot.org/uniprot/DHI1_MOUSE DHI1_MOUSE] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Indole-pyrrolidines were identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC(50) potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11beta-hydroxysteroid dehydrogenase type 2 (selectivity ratio &gt;200) and exhibited good inhibition of 11beta-HSD1 (IC(50)&lt;1muM) in a cellular model (3T3L1 adipocytes).
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Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11beta-hydroxysteroid dehydrogenase type I.,Valeur E, Christmann-Franck S, Lepifre F, Carniato D, Cravo D, Charon C, Bozec S, Musil D, Hillertz P, Doare L, Schmidlin F, Lecomte M, Schultz M, Roche D Bioorg Med Chem Lett. 2012 Sep 15;22(18):5909-14. doi:, 10.1016/j.bmcl.2012.07.070. Epub 2012 Jul 31. PMID:22901389<ref>PMID:22901389</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Hydroxysteroid dehydrogenase|Hydroxysteroid dehydrogenase]]
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*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: 11-beta-hydroxysteroid dehydrogenase]]
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[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
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[[Category: Christmann-Franck, S]]
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[[Category: Christmann-Franck S]]
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[[Category: Hillertz, P]]
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[[Category: Hillertz P]]
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[[Category: Lepifre, F]]
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[[Category: Lepifre F]]
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[[Category: Musil, D]]
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[[Category: Musil D]]
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[[Category: Roche, D]]
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[[Category: Roche D]]
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[[Category: Valeur, E]]
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[[Category: Valeur E]]
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[[Category: Alpha/beta]]
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[[Category: Endoplasmic reticulum]]
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[[Category: Glycoprotein]]
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[[Category: Lipid metabolism]]
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[[Category: Membrane]]
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[[Category: Nadp]]
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[[Category: Oxidoreductase]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Signal-anchor]]
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[[Category: Steroid metabolism]]
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[[Category: Transmembrane]]
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Structure-based design of 7-Azaindole-pyrrolidines as inhibitors of 11beta-Hydroxysteroid-Dehydrogenase type I

PDB ID 3gmd

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