2c3j: Difference between revisions

Inhibition of the Chk1 kinase by small molecules binding to its active, site is a strategy of great therapeutic interest for oncology. We report, how computational modelling predicted the binding mode of ligands of, special interest to the Chk1 ATP site, for representatives of an indazole, series and debromohymenialdisine. These binding modes were subsequently, confirmed by X-ray crystallography. The binding mode of a potent indazole, derivative involves non-conventional C-H...O and N-H...pi-aromatic, interactions with the protein. These interactions are formed in a buried, pocket at the periphery of the ATP-binding site, the importance of which, has previously been overlooked for ligand design against Chk1. It is, demonstrated that filling this pocket can confer ligands with dramatically, enhanced affinity for Chk1. Structural arguments in conjunction with assay, data explain why targeting this pocket is also advantageous for selective, binding to Chk1. Structural overlays of known inhibitors complexed with, Chk1 show that only the indazole series utilizes the pocket of interest., Therefore, the analysis presented here should prove helpful in guiding, future structure-based ligand design efforts against Chk1.

2C3J 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 SO3 and DBQ as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2C3J OCA].  

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