title: In silico and NMR identification of inhibitors of the IGF-I and IGF-binding protein-5 interaction.
abstract: Recently we have determined the crystal structure of the insulin-like growth factor-I (IGF-I) in complex with the N-terminal domain of the IGF-binding protein-5 (IGFBP-5). Here we report results of computer screening for potential inhibitors of this interaction using the crystal coordinates. From the compounds suggested by in silico screens, successful binders were identified by NMR spectroscopic methods. NMR was also used to map their binding sites and calculate their binding affinities. Small molecular weight compounds (FMOC derivatives) bind to the IGF-I binding site on the IGFBP-5 with micromolar affinities and thus serve as potential starting compounds for the design of more potent inhibitors and therapeutic agents for diseases that are associated with abnormal IGF-I regulation.
authors.affiliation: Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany. mariusz@mbi.ucla.edu
authors.forename: Mariusz
authors.initials: M
authors.lastname: Kamionka
authors.forename: Till
authors.initials: T
authors.lastname: Rehm
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Beisel
authors.forename: Kurt
authors.initials: K
authors.lastname: Lang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Engh
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D001665:Binding Sites; D005449:Fluorenes / Q000737:chemistry*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D005449:Fluorenes; D018975:Insulin-Like Growth Factor Binding Protein 5; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D007334:Insulin-Like Growth Factor I