1zzl
From Proteopedia
(New page: 200px<br /> <applet load="1zzl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zzl, resolution 2.000Å" /> '''Crystal structure ...) |
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| - | [[Image:1zzl.gif|left|200px]]<br /> | + | [[Image:1zzl.gif|left|200px]]<br /><applet load="1zzl" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1zzl" size=" | + | |
caption="1zzl, resolution 2.000Å" /> | caption="1zzl, resolution 2.000Å" /> | ||
'''Crystal structure of P38 with triazolopyridine'''<br /> | '''Crystal structure of P38 with triazolopyridine'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase | + | Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency. |
==About this Structure== | ==About this Structure== | ||
| - | 1ZZL 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 TZY as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http:// | + | 1ZZL 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=TZY:'>TZY</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZZL OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Han, S.]] | [[Category: Han, S.]] | ||
| - | [[Category: McClure, K | + | [[Category: McClure, K F.]] |
[[Category: TZY]] | [[Category: TZY]] | ||
[[Category: phosphorylation]] | [[Category: phosphorylation]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:20:36 2008'' |
Revision as of 14:20, 21 February 2008
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Crystal structure of P38 with triazolopyridine
Overview
Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.
About this Structure
1ZZL is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
Reference
Theoretical and experimental design of atypical kinase inhibitors: application to p38 MAP kinase., McClure KF, Abramov YA, Laird ER, Barberia JT, Cai W, Carty TJ, Cortina SR, Danley DE, Dipesa AJ, Donahue KM, Dombroski MA, Elliott NC, Gabel CA, Han S, Hynes TR, Lemotte PK, Mansour MN, Marr ES, Letavic MA, Pandit J, Ripin DB, Sweeney FJ, Tan D, Tao Y, J Med Chem. 2005 Sep 8;48(18):5728-37. PMID:16134941
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