title: Tyramine fragment binding to BACE-1.
abstract: Fragment screening revealed that tyramine binds to the active site of the Alzheimer's disease drug target BACE-1. Hit expansion by selection of compounds from the Roche compound library identified tyramine derivatives with improved binding affinities as monitored by surface plasmon resonance. X-ray structures show that the amine of the tyramine fragment hydrogen-bonds to the catalytic water molecule. Structure-guided ligand design led to the synthesis of further low molecular weight compounds that are starting points for chemical leads.
authors.affiliation: F. Hoffmann-La Roche, Pharma Research Basel, Grenzacherstr., 4070 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: Martin
authors.initials: M
authors.lastname: Stahl
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Peters
authors.forename: Walter
authors.initials: W
authors.lastname: Huber
authors.forename: Martine
authors.initials: M
authors.lastname: Stihle
authors.forename: Daniel
authors.initials: D
authors.lastname: Schlatter
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.forename: Armin
authors.initials: A
authors.lastname: Ruf
authors.forename: Doris
authors.initials: D
authors.lastname: Roth
authors.forename: Thilo
authors.initials: T
authors.lastname: Enderle
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D014439:Tyramine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D014439:Tyramine