Fragment based discovery of arginine isosteres through REPLACE: towards non-ATP competitive CDK inhibitors.

ABSTRACT: In order to develop non-ATP competitive CDK2/cyclin A inhibitors, the REPLACE strategy has been applied to generate fragment alternatives for the N-terminal tetrapeptide of the cyclin binding motif (HAKRRLIF) involved in substrate recruitment prior to phosphotransfer. The docking approach used for the prediction of small molecule mimics for peptide determinants was validated through reproduction of experimental binding modes of known inhibitors and provides useful information for evaluating binding to protein-protein interaction sites. Further to this, potential arginine isosteres predicted using the validated LigandFit docking method were ligated to the truncated C-terminal peptide, RLIF using solid phase synthesis and evaluated in a competitive binding assay. After testing, identified fr

SUBMITTER: Premnath PN 

PROVIDER: S-EPMC3917480 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature