Tyramine fragment binding to BACE-1.
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.
Kuglstatter
Andreas
A
F. Hoffmann-La Roche, Pharma Research Basel, Grenzacherstr., 4070 Basel, Switzerland.
Stahl
Martin
M
Peters
Jens-Uwe
JU
Huber
Walter
W
Stihle
Martine
M
Schlatter
Daniel
D
Benz
Jörg
J
Ruf
Armin
A
Roth
Doris
D
Enderle
Thilo
T
Hennig
Michael
M
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*
D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D014439:Tyramine