1wbt: Difference between revisions
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|SITE= <scene name='pdbsite=AC1:Wbt+Binding+Site+For+Chain+A'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Wbt+Binding+Site+For+Chain+A'>AC1</scene> | ||
|LIGAND= <scene name='pdbligand=WBT:3-FLUORO-5-MORPHOLIN-4-YL-N-[1-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-6-YL]BENZAMIDE'>WBT</scene> | |LIGAND= <scene name='pdbligand=WBT:3-FLUORO-5-MORPHOLIN-4-YL-N-[1-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-6-YL]BENZAMIDE'>WBT</scene> | ||
|ACTIVITY= [http://en.wikipedia.org/wiki/ | |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= | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1wbt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1wbt OCA], [http://www.ebi.ac.uk/pdbsum/1wbt PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1wbt 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]] | ||
[[Category: Non-specific serine/threonine protein kinase]] | |||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[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.]] | ||
[[Category: atp-binding]] | [[Category: atp-binding]] | ||
[[Category: direct protein sequencing]] | [[Category: direct protein sequencing]] | ||
| Line 37: | Line 39: | ||
[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:34:06 2008'' | ||
Revision as of 00:34, 31 March 2008
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| , resolution 2.00Å | |||||||
|---|---|---|---|---|---|---|---|
| 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.
OverviewOverview
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 StructureAbout this Structure
1WBT is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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
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