Thermodynamic and kinetic characterization of hydroxyethylamine β-secretase-1 inhibitors.
Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people. β-Secretase-1 (BACE-1), an enzyme involved in the processing of the amyloid precursor protein (APP) to form Aβ, is a well validated target for AD. Herein, the authors characterize 10 randomly selected hydroxyethylamine (HEA) BACE-1 inhibitors in terms of their association and dissociation rate constants and thermodynamics of binding using surface plasmon resonance (SPR). Rate constants of association (ka) measured at 25 °C ranged from a low of 2.42×10(4) M(-1) s(-1) to the highest value of 8.3×10(5) M(-1) s(-1). Rate constants of dissociation (kd) ranged from 1.09×10(-4) s(-1) (corresponding to a residence time of close to three hours), to the fastest of 0.028 s(-1). Three compounds were selected for further thermodynamic analysis where it was shown that equilibrium binding was enthalpy driven while unfavorable entropy of binding was observed. Structural analysis revealed that upon ligand binding, the BACE-1flap folds down over the bound ligand causing an induced fit. The maximal difference between alpha carbon positions in the open and closed conformations of the flap was over 5 Å. Thus the negative entropy of binding determined using SPR analysis was consistent with an induced fit observed by structural analysis.
Elan Pharmaceutical, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA.
Kalyani
K
Mondal
Karin
K
Regnstrom
Winse
W
Morishige
Robin
R
Barbour
Gary
G
Probst
Ying-Zi
YZ
Xu
Dean R
DR
Artis
Nanhua
N
Yao
Paul
P
Beroza
Michael P
MP
Bova
D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors / Q000737:chemistry; D004800:Enzymes, Immobilized / Q000037:antagonists & inhibitors / Q000737:chemistry; D004983:Ethanolamines; D006801:Humans; D007700:Kinetics; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013816:Thermodynamics
D004800:Enzymes, Immobilized; D004983:Ethanolamines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D057055:Aspartic Acid Proteases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Hydroxyethylamine; Kinetics; Residence time; SPR; Thermodynamics; β-Secretase