Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10757195 | Biochemical and Biophysical Research Communications | 2013 | 6 Pages |
Abstract
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 Ã 104 Mâ1 sâ1 to the highest value of 8.3 Ã 105 Mâ1 sâ1. Rate constants of dissociation (kd) ranged from 1.09 Ã 10â4 sâ1 (corresponding to a residence time of close to three hours), to the fastest of 0.028 sâ1. 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 Ã
. Thus the negative entropy of binding determined using SPR analysis was consistent with an induced fit observed by structural analysis.
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Authors
Kalyani Mondal, Karin Regnstrom, Winse Morishige, Robin Barbour, Gary Probst, Ying-Zi Xu, Dean R. Artis, Nanhua Yao, Paul Beroza, Michael P. Bova,