1ZZL
Crystal structure of P38 with triazolopyridine
Summary for 1ZZL
| Entry DOI | 10.2210/pdb1zzl/pdb |
| Descriptor | 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) |
| Functional Keywords | phosphorylation, serine/threonine-protein kinase, transferase |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm (By similarity): Q16539 |
| Total number of polymer chains | 1 |
| Total formula weight | 40585.38 |
| Authors | McClure, K.F.,Han, S. (deposition date: 2005-06-14, release date: 2005-09-13, Last modification date: 2024-02-14) |
| Primary citation | 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 Cited by 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: 16134941DOI: 10.1021/jm050346q PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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