title: Development of a potent Bcl-x(L) antagonist based on alpha-helix mimicry.
abstract: The rational design of low-molecular weight ligands that disrupt protein-protein interactions is still a challenging goal in medicinal chemistry. Our approach to this problem involves the design of molecular scaffolds that mimic the surface functionality projected along one face of an alpha-helix. Using a terphenyl scaffold, which in a staggered conformation closely reproduces the projection of functionality on the surface of an alpha-helix, we designed mimics of the pro-apoptotic alpha-helical Bak-peptide as inhibitors of the Bak/Bcl-xL interaction. This led to the development of a potent Bcl-xL antagonist (KD = 114 nM), whose binding affinity for Bcl-xL was assessed by a fluorescence polarization assay. To determine the binding site of the developed inhibitor we used docking studies and an HSQC-NMR experiment with 15N-labeled Bcl-xL protein. These studies suggest that the inhibitor is binding in the same hydrophobic cleft as the Bak- and Bad-peptides.
mesh_terms: D001665:Binding Sites; D005454:Fluorescence Polarization; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D017433:Protein Structure, Secondary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013730:Terphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013730:Terphenyl Compounds; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein