In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17β-HSD10 Inhibitors as Therapeutics in Alzheimer's Disease.
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.
1 School of Biology, University of St. Andrews, Medical and Biological Sciences Building, North Haugh, St. Andrews, Fife, UK.
Laura
L
Aitken
2 University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, Lanarkshire, UK.
Gemma
G
Baillie
2 University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, Lanarkshire, UK.
Andrew
A
Pannifer
2 University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, Lanarkshire, UK.
Angus
A
Morrison
2 University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, Lanarkshire, UK.
Philip S
PS
Jones
3 Biomedical Sciences Research Complex, University of St. Andrews, Biomolecular Sciences Building, North Haugh, St. Andrews, Fife, UK.
Terry K
TK
Smith
2 University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, Lanarkshire, UK.
Stuart P
SP
McElroy
1 School of Biology, University of St. Andrews, Medical and Biological Sciences Building, North Haugh, St. Andrews, Fife, UK.
Frank J
FJ
Gunn-Moore
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors*; D000544:Alzheimer Disease / Q000188:drug therapy; D055598:Chemical Phenomena; D055808:Drug Discovery / Q000379:methods; D057075:Enzyme Assays / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D011485:Protein Binding; D015203:Reproducibility of Results
D004791:Enzyme Inhibitors; D008024:Ligands; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human
enzyme assays or enzyme kinetics; ligand binding; neurodegenerative diseases; pharmacology; receptor binding; ultra-high-throughput screening