7jr6

From Proteopedia

(Difference between revisions)

Revision as of 03:49, 2 July 2021

H-PDGS complexed with a 2-phenylimidazo[1,2-a]pyridine-6-carboxamide inhibitors

Structural highlights

7jr6 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	6ztc
Gene:	HPGDS, GSTS, PGDS, PTGDS2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[HPGDS_HUMAN] 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] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.

A knowledge-based, structural-aided discovery of a novel class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors.,Deaton DN, Diaz E, Do Y, Gampe RT, Guss JH, Hancock AP, Hobbs H, Hodgson ST, Holt J, Jeune MR, Kahler KM, Kramer HF, Le J, Mortenson PN, Musetti C, Nolte RT, Orband-Miller LA, Peckham GE, Petrov KG, Pietrak BL, Poole C, Price DJ, Saxty G, Schulte CA, Shillings A, Smalley TL Jr, Somers DO, Stewart EL, Stuart JD, Thomson SA Bioorg Med Chem Lett. 2021 May 12:128113. doi: 10.1016/j.bmcl.2021.128113. PMID:33991628^[9]

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

References

↑ Kanaoka Y, Fujimori K, Kikuno R, Sakaguchi Y, Urade Y, Hayaishi O. Structure and chromosomal localization of human and mouse genes for hematopoietic prostaglandin D synthase. Conservation of the ancestral genomic structure of sigma-class glutathione S-transferase. Eur J Biochem. 2000 Jun;267(11):3315-22. PMID:10824118
↑ 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
↑ Suzuki T, Watanabe K, Kanaoka Y, Sato T, Hayaishi O. Induction of hematopoietic prostaglandin D synthase in human megakaryocytic cells by phorbol ester. Biochem Biophys Res Commun. 1997 Dec 18;241(2):288-93. PMID:9425264 doi:http://dx.doi.org/10.1006/bbrc.1997.7803
↑ Mahmud I, Ueda N, Yamaguchi H, Yamashita R, Yamamoto S, Kanaoka Y, Urade Y, Hayaishi O. Prostaglandin D synthase in human megakaryoblastic cells. J Biol Chem. 1997 Nov 7;272(45):28263-6. PMID:9353279
↑ Inoue T, Irikura D, Okazaki N, Kinugasa S, Matsumura H, Uodome N, Yamamoto M, Kumasaka T, Miyano M, Kai Y, Urade Y. Mechanism of metal activation of human hematopoietic prostaglandin D synthase. Nat Struct Biol. 2003 Apr;10(4):291-6. PMID:12627223 doi:10.1038/nsb907
↑ Inoue T, Okano Y, Kado Y, Aritake K, Irikura D, Uodome N, Okazaki N, Kinugasa S, Shishitani H, Matsumura H, Kai Y, Urade Y. First determination of the inhibitor complex structure of human hematopoietic prostaglandin D synthase. J Biochem. 2004 Mar;135(3):279-83. PMID:15113825
↑ 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
↑ Weber JE, Oakley AJ, Christ AN, Clark AG, Hayes JD, Hall R, Hume DA, Board PG, Smythe ML, Flanagan JU. Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D2 synthase. Eur J Med Chem. 2010 Feb;45(2):447-54. Epub 2009 Oct 23. PMID:19939518 doi:10.1016/j.ejmech.2009.10.025
↑ Deaton DN, Diaz E, Do Y, Gampe RT, Guss JH, Hancock AP, Hobbs H, Hodgson ST, Holt J, Jeune MR, Kahler KM, Kramer HF, Le J, Mortenson PN, Musetti C, Nolte RT, Orband-Miller LA, Peckham GE, Petrov KG, Pietrak BL, Poole C, Price DJ, Saxty G, Schulte CA, Shillings A, Smalley TL Jr, Somers DO, Stewart EL, Stuart JD, Thomson SA. A knowledge-based, structural-aided discovery of a novel class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors. Bioorg Med Chem Lett. 2021 May 12:128113. doi: 10.1016/j.bmcl.2021.128113. PMID:33991628 doi:http://dx.doi.org/10.1016/j.bmcl.2021.128113

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/7jr6"

@@ Line 1: / Line 1: @@
 ==H-PDGS complexed with a 2-phenylimidazo[1,2-a]pyridine-6-carboxamide inhibitors==
-<StructureSection load='7jr6' size='340' side='right'caption='[[7jr6]]' scene=''>
+<StructureSection load='7jr6' size='340' side='right'caption='[[7jr6]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JR6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JR6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7jr6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JR6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JR6 FirstGlance]. <br>
-</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=7jr6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jr6 OCA], [https://pdbe.org/7jr6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jr6 RCSB], [https://www.ebi.ac.uk/pdbsum/7jr6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jr6 ProSAT]</span></td></tr>
+</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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=VH4:1-(3-fluorophenyl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide'>VH4</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6ztc|6ztc]]</div></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HPGDS, GSTS, PGDS, PTGDS2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=7jr6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jr6 OCA], [https://pdbe.org/7jr6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jr6 RCSB], [https://www.ebi.ac.uk/pdbsum/7jr6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jr6 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[https://www.uniprot.org/uniprot/HPGDS_HUMAN HPGDS_HUMAN]] 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:10824118</ref> <ref>PMID:11672424</ref> <ref>PMID:9425264</ref> <ref>PMID:9353279</ref> <ref>PMID:12627223</ref> <ref>PMID:15113825</ref> <ref>PMID:16547010</ref> <ref>PMID:19939518</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.
+A knowledge-based, structural-aided discovery of a novel class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors.,Deaton DN, Diaz E, Do Y, Gampe RT, Guss JH, Hancock AP, Hobbs H, Hodgson ST, Holt J, Jeune MR, Kahler KM, Kramer HF, Le J, Mortenson PN, Musetti C, Nolte RT, Orband-Miller LA, Peckham GE, Petrov KG, Pietrak BL, Poole C, Price DJ, Saxty G, Schulte CA, Shillings A, Smalley TL Jr, Somers DO, Stewart EL, Stuart JD, Thomson SA Bioorg Med Chem Lett. 2021 May 12:128113. doi: 10.1016/j.bmcl.2021.128113. PMID:33991628<ref>PMID:33991628</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7jr6" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Gampe RT]]
+[[Category: Gampe, R T]]
-[[Category: Nolte RT]]
+[[Category: Nolte, R T]]
-[[Category: Somers DO]]
+[[Category: Somers, D O]]
+[[Category: Hematopoietic prostaglandin d2 synthase]]
+[[Category: Inhibitor]]
+[[Category: Isomerase]]
+[[Category: Transferase-inhibitor complex]]

7jr6

From Proteopedia

Revision as of 03:49, 2 July 2021

H-PDGS complexed with a 2-phenylimidazo[1,2-a]pyridine-6-carboxamide inhibitors

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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