6n69

From Proteopedia

(Difference between revisions)

Revision as of 06:44, 27 March 2019

rat hPGDS complexed with a quinoline

Structural highlights

6n69 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	6n4e
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pinzar E, Miyano M, Kanaoka Y, Urade Y, Hayaishi O. Structural basis of hematopoietic prostaglandin D synthase activity elucidated by site-directed mutagenesis. J Biol Chem. 2000 Oct 6;275(40):31239-44. PMID:10871602 doi:http://dx.doi.org/10.1074/jbc.M000750200
↑ Jowsey IR, Thomson AM, Flanagan JU, Murdock PR, Moore GB, Meyer DJ, Murphy GJ, Smith SA, Hayes JD. Mammalian class Sigma glutathione S-transferases: catalytic properties and tissue-specific expression of human and rat GSH-dependent prostaglandin D2 synthases. Biochem J. 2001 Nov 1;359(Pt 3):507-16. PMID:11672424
↑ Aritake K, Kado Y, Inoue T, Miyano M, Urade Y. Structural and functional characterization of HQL-79, an orally selective inhibitor of human hematopoietic prostaglandin D synthase. J Biol Chem. 2006 Jun 2;281(22):15277-86. Epub 2006 Mar 17. PMID:16547010 doi:10.1074/jbc.M506431200
↑ Kanaoka Y, Ago H, Inagaki E, Nanayama T, Miyano M, Kikuno R, Fujii Y, Eguchi N, Toh H, Urade Y, Hayaishi O. Cloning and crystal structure of hematopoietic prostaglandin D synthase. Cell. 1997 Sep 19;90(6):1085-95. PMID:9323136
↑ 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. The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors. Bioorg Med Chem. 2019 Apr 15;27(8):1456-1478. doi: 10.1016/j.bmc.2019.02.017., Epub 2019 Feb 11. PMID:30858025 doi:http://dx.doi.org/10.1016/j.bmc.2019.02.017

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6n69"

Categories: Large Structures | Cleasby, A | Shewchuk, L M | Hydrolase | Pgd2 synthase

@@ 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]] 2.00&Aring;' 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&reg;/PubMed&reg;, 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: Shewchuk, L M]]
+[[Category: Hydrolase]]
+[[Category: Pgd2 synthase]]

6n69

From Proteopedia

Revision as of 06:44, 27 March 2019

rat hPGDS complexed with a quinoline

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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