title: Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52.
abstract: FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products, which tightly bind to most FKBP family members, including FKBP51 and FKBP52. A bioisosteric replacement of the α-ketoamide moiety of rapamycin and FK506 with a sulfonamide was envisaged with the retention of the conserved hydrogen bonds. A focused solid support-based synthesis protocol was developed, which led to ligands with submicromolar affinity for FKBP51 and FKBP52. The molecular binding mode for one sulfonamide analogue was confirmed by X-ray crystallography.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Ranganath
authors.initials: R
authors.lastname: Gopalakrishnan
authors.forename: Christian
authors.initials: C
authors.lastname: Kozany
authors.forename: Yansong
authors.initials: Y
authors.lastname: Wang
authors.forename: Sabine
authors.initials: S
authors.lastname: Schneider
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Hoogeland
authors.forename: Andreas
authors.initials: A
authors.lastname: Bracher
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
mesh_terms: D018360:Crystallography, X-Ray; D005454:Fluorescence Polarization; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D010875:Pipecolic Acids; D013449:Sulfonamides; D016559:Tacrolimus; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C403485:tacrolimus binding protein 4