1zzl | pdb_00001zzl
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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 TZY 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
Page seeded by OCA on Mon Nov 12 20:43:31 2007
