1ZZL

Crystal structure of P38 with triazolopyridine

1ZZL の概要

• エントリーDOI: 10.2210/pdb1zzl/pdb
• 分子名称: Mitogen-activated protein kinase 14, 6-[4-(4-FLUOROPHENYL)-1,3-OXAZOL-5-YL]-3-ISOPROPYL[1,2,4]TRIAZOLO[4,3-A]PYRIDINE (3 entities in total)
• 機能のキーワード: phosphorylation, serine/threonine-protein kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm (By similarity): Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40585.38

構造登録者

McClure, K.F.,Han, S. (登録日: 2005-06-14, 公開日: 2005-09-13, 最終更新日: 2024-02-14)

主引用文献

McClure, K.F.,Abramov, Y.A.,Laird, E.R.,Barberia, J.T.,Cai, W.,Carty, T.J.,Cortina, S.R.,Danley, D.E.,Dipesa, A.J.,Donahue, K.M.,Dombroski, M.A.,Elliott, N.C.,Gabel, C.A.,Han, S.,Hynes, T.R.,Lemotte, P.K.,Mansour, M.N.,Marr, E.S.,Letavic, M.A.,Pandit, J.,Ripin, D.B.,Sweeney, F.J.,Tan, D.,Tao, Y.
Theoretical and Experimental Design of Atypical Kinase Inhibitors: Application to p38 MAP Kinase.
J.Med.Chem., 48:5728-5737, 2005

PubMed Abstract: 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.

PubMed: 16134941
DOI: 10.1021/jm050346q

実験手法

X-RAY DIFFRACTION (2 Å)