In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17β-HSD10 Inhibitors as Therapeutics in Alzheimer's Disease

Laura Aitken, Gemma Baillie, Andrew Pannifer, Angus Morrison, Philip S. Jones, Terry K. Smith, Stuart P. McElroy, Frank J. Gunn-Moore (Lead / Corresponding author)

Research output: Contribution to journalArticle

7 Citations (Scopus)
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Abstract

A major hallmark of Alzheimer's disease (AD) is the formation of neurotoxic aggregates composed of the amyloid-β peptide (Aβ). Aβ has been recognized to interact with numerous proteins, resulting in pathological changes to the metabolism of patients with AD. One such mitochondrial metabolic enzyme is amyloid-binding alcohol dehydrogenase (ABAD), where altered enzyme function caused by the Aβ-ABAD interaction is known to cause mitochondrial distress and cytotoxic effects, providing a feasible therapeutic target for AD drug development. Here we have established a high-throughput screening platform for the identification of modulators to the ABAD enzyme. A pilot screen with a total of 6759 compounds from the NIH Clinical Collections (NCC) and SelleckChem libraries and a selection of compounds from the BioAscent diversity collection have allowed validation and robustness to be optimized. The pilot screen revealed 16 potential inhibitors in the low µM range against ABAD with favorable physicochemical properties for blood-brain barrier penetration.

Original languageEnglish
Pages (from-to)676-685
Number of pages10
JournalSLAS Discovery
Volume22
Issue number6
Early online date17 Mar 2017
DOIs
Publication statusPublished - 1 Jul 2017

Keywords

  • Journal article
  • Enzyme assays or enzyme kinetics
  • Neurodegenerative diseases
  • Pharmacology
  • Ligand binding
  • Receptor binding
  • Ultra-high-throughput screening

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    Aitken, L., Baillie, G., Pannifer, A., Morrison, A., Jones, P. S., Smith, T. K., McElroy, S. P., & Gunn-Moore, F. J. (2017). In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17β-HSD10 Inhibitors as Therapeutics in Alzheimer's Disease. SLAS Discovery, 22(6), 676-685. https://doi.org/10.1177/2472555217697964