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5yea

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Revision as of 09:16, 21 October 2020

The crystal structure of Lp-PLA2 in complex with a novel inhibitor

Structural highlights

5yea is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	1-alkyl-2-acetylglycerophosphocholine esterase, with EC number 3.1.1.47
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PAFA_HUMAN] Defects in PLA2G7 are the cause of platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:614278]. An enzymatic deficiency that results in exacerbated bodily response to inflammatory agents. Asthmatic individuals affected by this condition may manifest severe respiratory symptoms.^[1] ^[2] ^[3] ^[4] ^[5] Defects in PLA2G7 are a cause of susceptibility to asthma (ASTHMA) [MIM:600807]. The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with weezing due to spasmodic contraction of the bronchi. Note=PLA2G7 variants can be a risk factor for the development of asthma and PLA2G7 may act as a modifier gene that modulates the severity of this disease.^[6] Defects in PLA2G7 are a cause of susceptibility to atopic hypersensitivity (ATOPY) [MIM:147050]. A condition characterized by predisposition to develop hypersensitivity reactions. Atopic individuals can develop eczema, allergic rhinitis and allergic asthma.^[7]

Function

[PAFA_HUMAN] Modulates the action of platelet-activating factor (PAF) by hydrolyzing the sn-2 ester bond to yield the biologically inactive lyso-PAF. Has a specificity for substrates with a short residue at the sn-2 position. It is inactive against long-chain phospholipids.

Publication Abstract from PubMed

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.

Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.,Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y J Med Chem. 2017 Dec 28;60(24):10231-10244. doi: 10.1021/acs.jmedchem.7b01530., Epub 2017 Dec 15. PMID:29193967^[8]

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

References

↑ Stafforini DM, Satoh K, Atkinson DL, Tjoelker LW, Eberhardt C, Yoshida H, Imaizumi T, Takamatsu S, Zimmerman GA, McIntyre TM, Gray PW, Prescott SM. Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase. J Clin Invest. 1996 Jun 15;97(12):2784-91. PMID:8675689 doi:10.1172/JCI118733
↑ Yamada Y, Yokota M. Loss of activity of plasma platelet-activating factor acetylhydrolase due to a novel Gln281-->Arg mutation. Biochem Biophys Res Commun. 1997 Jul 30;236(3):772-5. PMID:9245731 doi:S0006-291X(97)97047-9
↑ Hiramoto M, Yoshida H, Imaizumi T, Yoshimizu N, Satoh K. A mutation in plasma platelet-activating factor acetylhydrolase (Val279-->Phe) is a genetic risk factor for stroke. Stroke. 1997 Dec;28(12):2417-20. PMID:9412624
↑ Yamada Y, Ichihara S, Fujimura T, Yokota M. Identification of the G994--> T missense in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men. Metabolism. 1998 Feb;47(2):177-81. PMID:9472966
↑ Yoshida H, Imaizumi T, Fujimoto K, Itaya H, Hiramoto M, Yoshimizu N, Fukushi K, Satoh K. A mutation in plasma platelet-activating factor acetylhydrolase (Val279Phe) is a genetic risk factor for cerebral hemorrhage but not for hypertension. Thromb Haemost. 1998 Sep;80(3):372-5. PMID:9759612
↑ Kruse S, Mao XQ, Heinzmann A, Blattmann S, Roberts MH, Braun S, Gao PS, Forster J, Kuehr J, Hopkin JM, Shirakawa T, Deichmann KA. The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am J Hum Genet. 2000 May;66(5):1522-30. Epub 2000 Mar 24. PMID:10733466 doi:S0002-9297(07)62982-6
↑ Kruse S, Mao XQ, Heinzmann A, Blattmann S, Roberts MH, Braun S, Gao PS, Forster J, Kuehr J, Hopkin JM, Shirakawa T, Deichmann KA. The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am J Hum Genet. 2000 May;66(5):1522-30. Epub 2000 Mar 24. PMID:10733466 doi:S0002-9297(07)62982-6
↑ Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y. Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2. J Med Chem. 2017 Dec 28;60(24):10231-10244. doi: 10.1021/acs.jmedchem.7b01530., Epub 2017 Dec 15. PMID:29193967 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01530

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5yea"

@@ Line 1: / Line 1: @@
 ==The crystal structure of Lp-PLA2 in complex with a novel inhibitor==
-<StructureSection load='5yea' size='340' side='right' caption='[[5yea]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
+<StructureSection load='5yea' size='340' side='right'caption='[[5yea]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5yea]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YEA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YEA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5yea]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YEA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5YEA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8U9:4-[[4-[4-chloranyl-3-(trifluoromethyl)phenoxy]-3-cyano-phenyl]sulfamoyl]benzoic+acid'>8U9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8U9:4-[[4-[4-chloranyl-3-(trifluoromethyl)phenoxy]-3-cyano-phenyl]sulfamoyl]benzoic+acid'>8U9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/1-alkyl-2-acetylglycerophosphocholine_esterase 1-alkyl-2-acetylglycerophosphocholine esterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.47 3.1.1.47] </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=5yea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yea OCA], [http://pdbe.org/5yea PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yea RCSB], [http://www.ebi.ac.uk/pdbsum/5yea PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yea ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5yea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yea OCA], [http://pdbe.org/5yea PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yea RCSB], [http://www.ebi.ac.uk/pdbsum/5yea PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yea ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 26: / Line 26: @@
 </StructureSection>
 [[Category: 1-alkyl-2-acetylglycerophosphocholine esterase]]
+[[Category: Large Structures]]
 [[Category: Liu, Q F]]
 [[Category: Xu, Y C]]

5yea

From Proteopedia

Revision as of 09:16, 21 October 2020

The crystal structure of Lp-PLA2 in complex with a novel inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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