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[[ | ==p38 kinase Crystal structure in complex with small molecule inhibitor== | ||
<StructureSection load='3mw1' size='340' side='right' caption='[[3mw1]], [[Resolution|resolution]] 2.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mw1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MW1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MW1 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MIH:8-(2,6-DICHLOROPHENYL)-4-(2,4-DIFLUOROPHENYL)-2-PIPERIDIN-4-YL-1,7-NAPHTHYRIDINE+7-OXIDE'>MIH</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hrb|3hrb]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAPK14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=3mw1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mw1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mw1 RCSB], [http://www.ebi.ac.uk/pdbsum/3mw1 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The design, synthesis, and ability to inhibit p38alpha MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38alpha inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFalpha levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg). | |||
1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase.,Lumeras W, Vidal L, Vidal B, Balague C, Orellana A, Maldonado M, Dominguez M, Segarra V, Caturla F J Med Chem. 2011 Nov 24;54(22):7899-910. Epub 2011 Oct 31. PMID:21999461<ref>PMID:21999461</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]] | *[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Mitogen-activated protein kinase]] | [[Category: Mitogen-activated protein kinase]] | ||
[[Category: Caturla, F | [[Category: Caturla, F]] | ||
[[Category: Fisher, M | [[Category: Fisher, M]] | ||
[[Category: Lamers, M | [[Category: Lamers, M]] | ||
[[Category: Lumeras, W | [[Category: Lumeras, W]] | ||
[[Category: Roca, R | [[Category: Roca, R]] | ||
[[Category: Segarra, V | [[Category: Segarra, V]] | ||
[[Category: Inhibitor complex]] | [[Category: Inhibitor complex]] | ||
[[Category: P38 map kinase]] | [[Category: P38 map kinase]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
[[Category: Transferase-transferase inhibitor complex]] | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 12:48, 9 December 2014
p38 kinase Crystal structure in complex with small molecule inhibitorp38 kinase Crystal structure in complex with small molecule inhibitor
Structural highlights
Publication Abstract from PubMedThe design, synthesis, and ability to inhibit p38alpha MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38alpha inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFalpha levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg). 1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase.,Lumeras W, Vidal L, Vidal B, Balague C, Orellana A, Maldonado M, Dominguez M, Segarra V, Caturla F J Med Chem. 2011 Nov 24;54(22):7899-910. Epub 2011 Oct 31. PMID:21999461[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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