6n69 - Revision history

OCA at 14:46, 13 March 2024

OCA — Wed, 13 Mar 2024 14:46:46 GMT

←Older revision		Revision as of 14:46, 13 March 2024
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	<StructureSection load='6n69' size='340' side='right'caption='[[6n69]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='6n69' size='340' side='right'caption='[[6n69]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6n69]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Buffalo_rat Buffalo rat~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N69 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6N69 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6n69]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N69 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N69 FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name~~=~~'pdbligand=GSH:GLUTATHIONE'>GSH</scene~~>, ~~<scene name='pdbligand=KDV:quinoline-3-carbonitrile'>KDV</scene>~~</td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2Å</td></tr>
-	<tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~\|~~Related~~:]]</b></td><td class="sblockDat">~~[[6n4e\|6n4e]]~~<~~/td~~></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=KDV:quinoline-3-carbonitrile'>KDV</scene></td></tr>
-	<~~tr id~~='~~gene'><td class~~=~~"sblockLbl"><b>[[Gene\|Gene~~:~~]]</b~~></td>~~<td class="sblockDat">Hpgds, Gsts, Pgds, Ptgds2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])~~</td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6n69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n69 OCA], [https://pdbe.org/6n69 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n69 RCSB], [https://www.ebi.ac.uk/pdbsum/6n69 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n69 ProSAT]</span></td></tr>
-	<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=6n69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n69 OCA], [~~http~~://pdbe.org/6n69 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6n69 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6n69 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6n69 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/HPGDS_RAT HPGDS_RAT]] Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.<ref>PMID:10871602</ref> <ref>PMID:11672424</ref> <ref>PMID:16547010</ref> <ref>PMID:9323136</ref>	+	[https://www.uniprot.org/uniprot/HPGDS_RAT HPGDS_RAT] Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.<ref>PMID:10871602</ref> <ref>PMID:11672424</ref> <ref>PMID:16547010</ref> <ref>PMID:9323136</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50=220,000nM, LE=0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50=3,100nM, LE=0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50=9.9nM, LE=0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.	+

-	The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.,Deaton DN, Do Y, Holt J, Jeune MR, Kramer HF, Larkin AL, Orband-Miller LA, Peckham GE, Poole C, Price DJ, Schaller LT, Shen Y, Shewchuk LM, Stewart EL, Stuart JD, Thomson SA, Ward P, Wilson JW, Xu T, Guss JH, Musetti C, Rendina AR, Affleck K, Anders D, Hancock AP, Hobbs H, Hodgson ST, Hutchinson J, Leveridge MV, Nicholls H, Smith IED, Somers DO, Sneddon HF, Uddin S~~, Cleasby A, Mortenson PN, Richardson C, Saxty G Bioorg Med Chem. 2019 Apr 15;27(8):1456~~-~~1478. doi: 10.1016/j.bmc.2019.02.017., Epub 2019 Feb 11. PMID:30858025<ref>PMID:30858025</ref>~~	+	==See Also==
-		+	*[[Glutathione S-transferase 3D structures\|Glutathione S-transferase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.~~S~~. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6n69" style="background~~-~~color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Buffalo rat]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Cleasby, A~~]]	+	[[Category: Rattus norvegicus]]
-	[[Category: ~~Shewchuk, L M~~]]	+	[[Category: Cleasby A]]
-	[[Category: ~~Hydrolase]]~~	+	[[Category: Shewchuk LM]]
-	~~[[Category: Pgd2 synthase~~]]	+

OCA at 07:58, 10 April 2019

OCA — Wed, 10 Apr 2019 07:58:03 GMT

←Older revision		Revision as of 07:58, 10 April 2019
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	<StructureSection load='6n69' size='340' side='right'caption='[[6n69]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='6n69' size='340' side='right'caption='[[6n69]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6n69]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N69 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N69 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6n69]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N69 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N69 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=KDV:quinoline-3-carbonitrile'>KDV</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=KDV:quinoline-3-carbonitrile'>KDV</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6n4e\|6n4e]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6n4e\|6n4e]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Hpgds, Gsts, Pgds, Ptgds2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
	<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=6n69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n69 OCA], [http://pdbe.org/6n69 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n69 RCSB], [http://www.ebi.ac.uk/pdbsum/6n69 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n69 ProSAT]</span></td></tr>		<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=6n69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n69 OCA], [http://pdbe.org/6n69 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n69 RCSB], [http://www.ebi.ac.uk/pdbsum/6n69 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n69 ProSAT]</span></td></tr>
	</table>		</table>
Line 23:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Buffalo rat]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Cleasby, A]]		[[Category: Cleasby, A]]

OCA at 06:44, 27 March 2019

OCA — Wed, 27 Mar 2019 06:44:32 GMT

←Older revision		Revision as of 06:44, 27 March 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6n69 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==rat hPGDS complexed with a quinoline==
		+	<StructureSection load='6n69' size='340' side='right'caption='[[6n69]], [[Resolution\|resolution]] 2.00Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6n69]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N69 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N69 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=KDV:quinoline-3-carbonitrile'>KDV</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6n4e\|6n4e]]</td></tr>
		+	<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=6n69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n69 OCA], [http://pdbe.org/6n69 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n69 RCSB], [http://www.ebi.ac.uk/pdbsum/6n69 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n69 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/HPGDS_RAT HPGDS_RAT]] Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.<ref>PMID:10871602</ref> <ref>PMID:11672424</ref> <ref>PMID:16547010</ref> <ref>PMID:9323136</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50=220,000nM, LE=0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50=3,100nM, LE=0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50=9.9nM, LE=0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.

-	~~Authors:~~ Shewchuk, ~~L.M.~~, ~~Cleasby~~, A.	+	The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.,Deaton DN, Do Y, Holt J, Jeune MR, Kramer HF, Larkin AL, Orband-Miller LA, Peckham GE, Poole C, Price DJ, Schaller LT, Shen Y, Shewchuk LM, Stewart EL, Stuart JD, Thomson SA, Ward P, Wilson JW, Xu T, Guss JH, Musetti C, Rendina AR, Affleck K, Anders D, Hancock AP, Hobbs H, Hodgson ST, Hutchinson J, Leveridge MV, Nicholls H, Smith IED, Somers DO, Sneddon HF, Uddin S, Cleasby A, Mortenson PN, Richardson C, Saxty G Bioorg Med Chem. 2019 Apr 15;27(8):1456-1478. doi: 10.1016/j.bmc.2019.02.017., Epub 2019 Feb 11. PMID:30858025<ref>PMID:30858025</ref>

-	~~Description: rat hPGDS complexed with~~ a ~~quinoline~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
-	[[Category: ~~Shewchuk, L.M~~]]	+	<div class="pdbe-citations 6n69" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Cleasby, A]]		[[Category: Cleasby, A]]
		+	[[Category: Shewchuk, L M]]
		+	[[Category: Hydrolase]]
		+	[[Category: Pgd2 synthase]]

OCA at 10:33, 16 January 2019

OCA — Wed, 16 Jan 2019 10:33:47 GMT

←Older revision		Revision as of 10:33, 16 January 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6n69 is ON HOLD	+	The entry 6n69 is ON HOLD until Paper Publication

	Authors: Shewchuk, L.M., Cleasby, A.		Authors: Shewchuk, L.M., Cleasby, A.

OCA: Protected "6n69" [edit=sysop:move=sysop]

OCA — Wed, 05 Dec 2018 05:16:26 GMT

Protected "6n69" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:16, 5 December 2018

OCA: New page: '''Unreleased structure''' The entry 6n69 is ON HOLD Authors: Shewchuk, L.M., Cleasby, A. Description: rat hPGDS complexed with a quinoline Category: Unreleased Structures [[Catego...

OCA — Wed, 05 Dec 2018 05:16:25 GMT

New page: '''Unreleased structure''' The entry 6n69 is ON HOLD Authors: Shewchuk, L.M., Cleasby, A. Description: rat hPGDS complexed with a quinoline Category: Unreleased Structures [[Catego...

New page

'''Unreleased structure'''

The entry 6n69 is ON HOLD

Authors: Shewchuk, L.M., Cleasby, A.

Description: rat hPGDS complexed with a quinoline
[[Category: Unreleased Structures]]
[[Category: Shewchuk, L.M]]
[[Category: Cleasby, A]]