Binding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors

Van der Westhuizen, CJVan Greunen, DGCordier, WNell, MSteenkamp, VStander, APanayides, Jenny-LeeRiley, DL2021-03-102021-03-102020-11Van der Westhuizen, C., Van Greunen, D., Cordier, W., Nell, M., Steenkamp, V., Stander, A., Panayides, J. & Riley, D. et al. 2020. Binding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors. ARKIVOC, Part V. http://hdl.handle.net/10204/118901551-70041551-7012http://hdl.handle.net/10204/11890ß-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 ß-secretase with a cytotoxicity IC50 value of 10.51 ± 1.11 µM against the SH-SY5Y cell line.FulltextenAlzheimer’s diseaseß-secretaseHydroxyethylamineInduced fit dockingMolecular dynamicsBinding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitorsArticleVan der Westhuizen, C., Van Greunen, D., Cordier, W., Nell, M., Steenkamp, V., Stander, A., ... Riley, D. (2020). Binding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors. ARKIVOC, Part V, http://hdl.handle.net/10204/11890Van der Westhuizen, CJ, DG Van Greunen, W Cordier, M Nell, V Steenkamp, A Stander, Jenny-Lee Panayides, and DL Riley "Binding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors." ARKIVOC, Part V (2020) http://hdl.handle.net/10204/11890Van der Westhuizen C, Van Greunen D, Cordier W, Nell M, Steenkamp V, Stander A, et al. Binding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors. ARKIVOC, Part V. 2020; http://hdl.handle.net/10204/11890.TY - Article AU - Van der Westhuizen, CJ AU - Van Greunen, DG AU - Cordier, W AU - Nell, M AU - Steenkamp, V AU - Stander, A AU - Panayides, Jenny-Lee AU - Riley, DL AB - ß-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 ß-secretase with a cytotoxicity IC50 value of 10.51 ± 1.11 µM against the SH-SY5Y cell line. DA - 2020-11 DB - ResearchSpace DP - CSIR J1 - ARKIVOC, Part V KW - Alzheimer’s disease KW - ß-secretase KW - Hydroxyethylamine KW - Induced fit docking KW - Molecular dynamics LK - https://researchspace.csir.co.za PY - 2020 SM - 1551-7004 SM - 1551-7012 T1 - Binding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors TI - Binding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors UR - http://hdl.handle.net/10204/11890 ER -24362