Design, synthesis, and validation of a β-turn mimetic library targeting protein-protein and peptide-receptor interactions.

ABSTRACT: The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library targeting the major recognition motifs involved in protein-protein interactions is described. Analysis of a geometric characterization of 10,245 β-turns in the protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (K(i) = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capa

SUBMITTER: Whitby LR 

PROVIDER: S-EPMC3134394 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature