1w82
From Proteopedia
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|PDB= 1w82 |SIZE=350|CAPTION= <scene name='initialview01'>1w82</scene>, resolution 2.20Å | |PDB= 1w82 |SIZE=350|CAPTION= <scene name='initialview01'>1w82</scene>, resolution 2.20Å | ||
|SITE= <scene name='pdbsite=AC1:L10+Binding+Site+For+Chain+A'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:L10+Binding+Site+For+Chain+A'>AC1</scene> | ||
| - | |LIGAND= <scene name='pdbligand=L10:N-[(3Z)-5-TERT-BUTYL-2-PHENYL-1,2-DIHYDRO-3H-PYRAZOL-3-YLIDENE]-N | + | |LIGAND= <scene name='pdbligand=L10:N-[(3Z)-5-TERT-BUTYL-2-PHENYL-1,2-DIHYDRO-3H-PYRAZOL-3-YLIDENE]-N'-(4-CHLOROPHENYL)UREA'>L10</scene> |
|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] | |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] | ||
|GENE= | |GENE= | ||
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[[Category: p38]] | [[Category: p38]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 23 14:04:55 2008'' |
Revision as of 12:04, 23 March 2008
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| , resolution 2.20Å | |||||||
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| Activity: | Transferred entry: 2.7.11.1, with EC number 2.7.1.37 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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
1W82 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
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