Binding pose analysis of hydroxyethylamine based β-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors
Loading...
Date
Authors
Van der Westhuizen, Carl Johan
Van Greunen, D.G. (Divan)
Cordier, Werner
Nell, Margo Judith
Steenkamp, Vanessa
Stander, Andre
Panayides, Jenny-Lee
Riley, Darren Lyall
Journal Title
Journal ISSN
Volume Title
Publisher
ARKAT
Abstract
β-Secretase (BACE1) is recognised as a target for the treatment of Alzheimer’s disease, and transition-state
isosteres such as hydroxyethylamines have shown promise when incorporated into BACE1 inhibitors. A
computational investigation of previously reported carbazole-based hydroxylethylamines with contradictory
binding poses was undertaken using molecular dynamic simulations to rationalise the ligands preferred
binding preference. Visual inspection of the confirmed binding pocket showed unoccupied space surrounding
the carbazole moiety which was probed through the synthesis of seventeen ligands wherein the carbazole ring
system was replaced with an indeno[1,2-b]indole ring system. The most active compound, rac-1-
[benzyl(methyl)amino]-3-(indeno[1,2-b]indol-5(10H)-yl)propan-2-ol, indicated an inhibition of 91% at 10 µM
against β-secretase with a cytotoxicity IC50 value of 10.51 ± 1.11 µM against the SH-SY5Y cell line.
Description
Keywords
Alzheimer’s disease, β-secretase, Hydroxyethylamine, Induced fit docking, Molecular dynamics
Sustainable Development Goals
Citation
Van der Westhuizen, J.C., Van Greunen, D.G., Cordier, W. et al. 2020, 'Binding pose analysis of hydroxyethylamine based β-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors', Arkivoc, vol. 2020, part v, pp. 84-107.