2wmq

CRYSTAL STRUCTURE OF CHECKPOINT KINASE 1 (CHK1) IN COMPLEX WITH INHIBITORSCRYSTAL STRUCTURE OF CHECKPOINT KINASE 1 (CHK1) IN COMPLEX WITH INHIBITORS

Structural highlights 2wmq is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Related: 2cgx, 2bro, 2c3j, 2brb, 2brh, 2cgv, 2c3k, 1nvr, 2cgw, 1zlt, 2brn, 2ayp, 1zys, 2cgu, 1ia8, 2br1, 2brg, 1nvs, 2brm, 1nvq, 2c3l, 2wmt, 2wmx, 2wmv, 2wms, 2wmw, 2wmu, 2wmr Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, RCSB, PDBsum Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Checkpoint kinase 1 (CHK1) is an oncology target of significant current interest. Inhibition of CHK1 abrogates DNA damage-induced cell cycle checkpoints and sensitizes p53 deficient cancer cells to genotoxic therapies. Using template screening, a fragment-based approach to small molecule hit generation, we have identified multiple CHK1 inhibitor scaffolds suitable for further optimization. The sequential combination of in silico low molecular weight template selection, a high concentration biochemical assay and hit validation through protein-ligand X-ray crystallography provided 13 template hits from an initial in silico screening library of ca. 15000 compounds. The use of appropriate counter-screening to rule out nonspecific aggregation by test compounds was essential for optimum performance of the high concentration bioassay. One low molecular weight, weakly active purine template hit was progressed by iterative structure-based design to give submicromolar pyrazolopyridines with good ligand efficiency and appropriate CHK1-mediated cellular activity in HT29 colon cancer cells. Identification of inhibitors of checkpoint kinase 1 through template screening.,Matthews TP, Klair S, Burns S, Boxall K, Cherry M, Fisher M, Westwood IM, Walton MI, McHardy T, Cheung KM, Van Montfort R, Williams D, Aherne GW, Garrett MD, Reader J, Collins I J Med Chem. 2009 Aug 13;52(15):4810-9. PMID:19572549 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase

spinqualitylabelsall models 2wmq, resolution 2.48Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image