1w83

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spinqualitylabelsall models 1w83, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 ... [(full description)]

About this Structure

1W83 is a [Single protein] structure of sequence from [Homo sapiens] with L11 as [ligand]. Active as [[1]], with EC number [2.7.1.37]. 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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