1w83

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[[Image:1w83.gif|left|200px]]
[[Image:1w83.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 1w83 |SIZE=350|CAPTION= <scene name='initialview01'>1w83</scene>, resolution 2.50&Aring;
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The line below this paragraph, containing "STRUCTURE_1w83", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:L11+Binding+Site+For+Chain+A'>AC1</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=L11:N-[4-CHLORO-3-(PYRIDIN-3-YLOXYMETHYL)-PHENYL]-3-FLUORO-'>L11</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE=
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-->
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|DOMAIN=
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{{STRUCTURE_1w83| PDB=1w83 | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1w83 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1w83 OCA], [http://www.ebi.ac.uk/pdbsum/1w83 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1w83 RCSB]</span>
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}}
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'''P38 KINASE CRYSTAL STRUCTURE IN COMPLEX WITH SMALL MOLECULE INHIBITOR'''
'''P38 KINASE CRYSTAL STRUCTURE IN COMPLEX WITH SMALL MOLECULE INHIBITOR'''
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[[Category: Jhoti, H.]]
[[Category: Jhoti, H.]]
[[Category: Tickle, J.]]
[[Category: Tickle, J.]]
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[[Category: inhibitor complex]]
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[[Category: Inhibitor complex]]
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[[Category: kinase]]
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[[Category: Kinase]]
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[[Category: p38]]
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[[Category: P38]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 13:17:11 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:32:30 2008''
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Revision as of 10:17, 3 May 2008

Image:1w83.gif

Template:STRUCTURE 1w83

P38 KINASE CRYSTAL STRUCTURE IN COMPLEX WITH SMALL MOLECULE INHIBITOR


Overview

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.

About this Structure

1W83 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation., Gill AL, Frederickson M, Cleasby A, Woodhead SJ, Carr MG, Woodhead AJ, Walker MT, Congreve MS, Devine LA, Tisi D, O'Reilly M, Seavers LC, Davis DJ, Curry J, Anthony R, Padova A, Murray CW, Carr RA, Jhoti H, J Med Chem. 2005 Jan 27;48(2):414-26. PMID:15658855 Page seeded by OCA on Sat May 3 13:17:11 2008

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