1wbw

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|SITE= <scene name='pdbsite=AC1:Li4+Binding+Site+For+Chain+A'>AC1</scene>
|SITE= <scene name='pdbsite=AC1:Li4+Binding+Site+For+Chain+A'>AC1</scene>
|LIGAND= <scene name='pdbligand=LI4:3-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINE'>LI4</scene>
|LIGAND= <scene name='pdbligand=LI4:3-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINE'>LI4</scene>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37]
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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>
|GENE=
|GENE=
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|DOMAIN=
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1wbw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1wbw OCA], [http://www.ebi.ac.uk/pdbsum/1wbw PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1wbw RCSB]</span>
}}
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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:[http://www.ncbi.nlm.nih.gov/pubmed/15658855 15658855]
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:[http://www.ncbi.nlm.nih.gov/pubmed/15658855 15658855]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: Transferred entry: 2 7.11 1]]
 
[[Category: Cleasby, A.]]
[[Category: Cleasby, A.]]
[[Category: Devine, L A.]]
[[Category: Devine, L A.]]
[[Category: Jhoti, H.]]
[[Category: Jhoti, H.]]
[[Category: Tickle, J.]]
[[Category: Tickle, J.]]
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[[Category: LI4]]
 
[[Category: alternative splicing]]
[[Category: alternative splicing]]
[[Category: atp-binding]]
[[Category: atp-binding]]
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[[Category: transferase]]
[[Category: transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:54:58 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:34:06 2008''

Revision as of 21:34, 30 March 2008

Image:1wbw.gif


PDB ID 1wbw

Drag the structure with the mouse to rotate
, resolution 2.41Å
Sites:
Ligands:
Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



IDENTIFICATION OF NOVEL P38 ALPHA MAP KINASE INHIBITORS USING FRAGMENT-BASED LEAD GENERATION.


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

1WBW 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 Mon Mar 31 00:34:06 2008

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