title: 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 fragments were shown to represent not only appropriate mimics for a critical arginine residue but also to interact effectively with a minor hydrophobic pocket present in the binding groove. Further evaluation of binding modes was undertaken to optimize the potency of these compounds. Through further application of the REPLACE strategy in this study, peptide-small molecule hybrid CDK2 inhibitors were identified that are more drug-like and suitable for further optimization as anti-tumor therapeutics.
authors.affiliation: Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: Padmavathy Nandha
authors.initials: PN
authors.lastname: Premnath
authors.affiliation: Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: Tracy
authors.initials: T
authors.lastname: Perkins
authors.affiliation: Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Abbott
authors.affiliation: Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Anderson
authors.affiliation: Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States. Electronic address: mcinnes@sccp.sc.edu.
authors.forename: Campbell
authors.initials: C
authors.lastname: McInnes
mesh_terms: D001120:Arginine / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry*; D016213:Cyclins / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D016213:Cyclins; D047428:Protein Kinase Inhibitors; D001120:Arginine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: Anti-tumor therapeutic; Cyclin dependent kinase; Drug discovery; Inhibitor; REPLACE