title: Optimization of non-ATP competitive CDK/cyclin groove inhibitors through REPLACE-mediated fragment assembly.
abstract: A major challenge in drug discovery is to develop and improve methods for targeting protein-protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generating inhibitors of protein-protein interactions demonstrated that it can be used to optimize fragment alternatives of key determinants, to combine these in an effective way, and this was achieved for compounds targeting the cyclin-dependent kinase 2 (CDK2) substrate recruitment site on the cyclin regulatory subunit. Phenylheterocyclic isosteres replacing a critical charge-charge interaction provided new structural insights for binding to the cyclin groove. In particular, these results shed light onto the key contributions of a H-bond observed in crystal structures of N-terminally capped peptides. Furthermore, the structure-activity relationship of a bis(aryl) ether C-terminal capping group mimicking dipeptide interactions was probed through ring substitutions, allowing increased complementarity with the primary hydrophobic pocket. This study further validates REPLACE as an effective strategy for converting peptidic compounds to more pharmaceutically relevant compounds.
authors: Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States.
authors: Shu
authors: S
authors: Liu
authors: Padmavathy Nandha
authors: PN
authors: Premnath
authors: Joshua K
authors: JK
authors: Bolger
authors: Tracy L
authors: TL
authors: Perkins
authors: Lindsay O
authors: LO
authors: Kirkland
authors: George
authors: G
authors: Kontopidis
authors: Campbell
authors: C
authors: McInnes
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D004151:Dipeptides; D008024:Ligands; D009842:Oligopeptides; D057786:Peptidomimetics; D011720:Pyrazoles; D011758:Pyrroles; D014230:Triazoles; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases