5bqh

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==Discovery of a Potent and Selective mPGES-1 Inhibitor for the Treatment of Pain==
==Discovery of a Potent and Selective mPGES-1 Inhibitor for the Treatment of Pain==
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<StructureSection load='5bqh' size='340' side='right' caption='[[5bqh]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
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<StructureSection load='5bqh' size='340' side='right'caption='[[5bqh]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5bqh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BQH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BQH FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5bqh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BQH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BQH 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=1KA:(2-HYDROXYETHOXY)ACETALDEHYDE'>1KA</scene>, <scene name='pdbligand=4UK:N-[4-(4-CHLOROPHENYL)-1H-IMIDAZOL-2-YL]-2-(DIFLUOROMETHYL)-5-{[(2-METHYLPROPANOYL)AMINO]METHYL}BENZAMIDE'>4UK</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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]] 1.601&#8491;</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/Prostaglandin-E_synthase Prostaglandin-E synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.99.3 5.3.99.3] </span></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=1KA:(2-HYDROXYETHOXY)ACETALDEHYDE'>1KA</scene>, <scene name='pdbligand=4UK:N-[4-(4-CHLOROPHENYL)-1H-IMIDAZOL-2-YL]-2-(DIFLUOROMETHYL)-5-{[(2-METHYLPROPANOYL)AMINO]METHYL}BENZAMIDE'>4UK</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></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=5bqh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bqh OCA], [http://pdbe.org/5bqh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bqh RCSB], [http://www.ebi.ac.uk/pdbsum/5bqh PDBsum]</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=5bqh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bqh OCA], [https://pdbe.org/5bqh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bqh RCSB], [https://www.ebi.ac.uk/pdbsum/5bqh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bqh ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/PTGES_HUMAN PTGES_HUMAN]] Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).<ref>PMID:18682561</ref>
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[https://www.uniprot.org/uniprot/PTGES_HUMAN PTGES_HUMAN] Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).<ref>PMID:18682561</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 muM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8.H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.
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Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.,Schiffler MA, Antonysamy S, Bhattachar SN, Campanale KM, Chandrasekhar S, Condon B, Desai PV, Fisher MJ, Groshong C, Harvey A, Hickey MJ, Hughes NE, Jones SA, Kim EJ, Kuklish SL, Luz JG, Norman BH, Rathmell RE, Rizzo JR, Seng TW, Thibodeaux SJ, Woods TA, York JS, Yu XP J Med Chem. 2016 Jan 14;59(1):194-205. doi: 10.1021/acs.jmedchem.5b01249. Epub, 2015 Dec 18. PMID:26653180<ref>PMID:26653180</ref>
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==See Also==
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*[[Prostaglandin E synthase|Prostaglandin E synthase]]
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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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<div class="pdbe-citations 5bqh" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Prostaglandin-E synthase]]
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[[Category: Homo sapiens]]
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[[Category: Antonysamy, S]]
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[[Category: Large Structures]]
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[[Category: Fisher, M J]]
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[[Category: Antonysamy S]]
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[[Category: Kuklish, S L]]
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[[Category: Fisher MJ]]
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[[Category: Luz, J G]]
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[[Category: Kuklish SL]]
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[[Category: Schiffler, M A]]
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[[Category: Luz JG]]
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[[Category: Enzyme]]
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[[Category: Schiffler MA]]
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[[Category: Integral membrane protein]]
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[[Category: Isomerase-isomerase inhibitor complex]]
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[[Category: Mpges-1]]
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Current revision

Discovery of a Potent and Selective mPGES-1 Inhibitor for the Treatment of Pain

PDB ID 5bqh

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