1wbt: Difference between revisions
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[[Image:1wbt.gif|left|200px]]<br /><applet load="1wbt" size=" | [[Image:1wbt.gif|left|200px]]<br /><applet load="1wbt" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1wbt, resolution 2.00Å" /> | caption="1wbt, resolution 2.00Å" /> | ||
'''IDENTIFICATION OF NOVEL P38 ALPHA MAP KINASE INHIBITORS USING FRAGMENT-BASED LEAD GENERATION.'''<br /> | '''IDENTIFICATION OF NOVEL P38 ALPHA MAP KINASE INHIBITORS USING FRAGMENT-BASED LEAD GENERATION.'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
1WBT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with WBT as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Known structural/functional Site: <scene name='pdbsite=AC1:Wbt Binding Site For Chain A'>AC1</scene>. Full crystallographic information is available from [http:// | 1WBT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=WBT:'>WBT</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Known structural/functional Site: <scene name='pdbsite=AC1:Wbt+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1WBT OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb 3 10:21:34 2008'' | ||
Revision as of 11:21, 3 February 2008
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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 with as ligand. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Known structural/functional Site: . 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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