title: Structure-Affinity Relationship Analysis of Selective FKBP51 Ligands.
abstract: The FK506-binding protein 51 (FKBP51) is a promising drug target for the treatment of stress-related psychiatric or metabolic disorders. Just recently, the first selective ligands for FKBP51 were reported based on an induced fit mechanism, but they are too large for a further drug development process. We therefore designed and synthesized a novel series of selective ligands to explore the requirements necessary for binding to the induced-fit conformation. All ligands of this series show no binding toward the structurally very similar antitarget FKBP52. With the cocrystal structure of the best ligand in this novel series we confirmed the induced fit mechanism. Furthermore, the structure-affinity relationship provides information about beneficial structural features, which is valuable for the development of improved FKBP51-directed drugs.
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Xixi
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sippel
authors.affiliation: Max Planck Institute of Biochemistry , Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bracher
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
mesh_terms: D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D008024:Ligands; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D013329:Structure-Activity Relationship; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D008024:Ligands; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5