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Title: Thermodynamic and kinetic characterization of hydroxyethylamine β-secretase-1 inhibitors

Highlights: •Kinetic and thermodynamic characterization of 10 hydroxyethylamine BACE-1 inhibitors. •Equilibrium binding of inhibitors was enthalpy driven for BACE-1. •Negative entropy of binding was observed towards BACE-1, but not Cathepsin-D. •Structural analysis demonstrates ligand binding induces a major conformational change. •Structural analysis and SPR analysis corroborate induced fit and negative entropy of binding. -- 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 (k{sub a}) measured at 25 °C ranged from a low of 2.42 × 10{sup 4} M{sup −1} s{sup −1} to the highest value of 8.3 × 10{sup 5} M{sup −1} s{sup −1}. Rate constants of dissociation (k{sub d}) ranged from 1.09 × 10{sup −4} s{sup −1} (corresponding to a residence time of close to three hours), to the fastest of 0.028 s{sup −1}. Three compounds were selected for further thermodynamic analysis where it was shown thatmore » 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.« less
Authors:
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Publication Date:
OSTI Identifier:
22242186
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 441; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; CATHEPSINS; CONFORMATIONAL CHANGES; DISSOCIATION; ENTHALPY; ENTROPY; LIGANDS; NERVOUS SYSTEM DISEASES; REACTION KINETICS; THERMODYNAMICS