1w83: Difference between revisions
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==Overview== | ==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 | 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== | ==About this Structure== | ||
1W83 is a | 1W83 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 L11 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] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1W83 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: p38]] | [[Category: p38]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:07:27 2007'' | ||
