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

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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

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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.

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Keywords

Alzheimer’s disease, β-secretase, Hydroxyethylamine, Induced fit docking, Molecular dynamics

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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.