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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

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dc.contributor.author Van der Westhuizen, CJ
dc.contributor.author Van Greunen, DG
dc.contributor.author Cordier, W
dc.contributor.author Nell, M
dc.contributor.author Steenkamp, V
dc.contributor.author Stander, A
dc.contributor.author Panayides, Jenny-Lee
dc.contributor.author Riley, DL
dc.date.accessioned 2021-03-10T15:22:53Z
dc.date.available 2021-03-10T15:22:53Z
dc.date.issued 2020-11
dc.identifier.citation Van 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. <i>ARKIVOC, Part V.</i> http://hdl.handle.net/10204/11890 en_ZA
dc.identifier.issn 1551-7004
dc.identifier.issn 1551-7012
dc.identifier.uri http://hdl.handle.net/10204/11890
dc.description.abstract 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. en_US
dc.format Fulltext en_US
dc.language.iso en en_US
dc.relation.uri DOI: https://doi.org/10.24820/ark.5550190.p011.350 en_US
dc.relation.uri https://www.arkat-usa.org/arkivoc-journal/browse-arkivoc/ark.5550190.p011.350 en_US
dc.source ARKIVOC, Part V en_US
dc.subject Alzheimer’s disease en_US
dc.subject ß-secretase en_US
dc.subject Hydroxyethylamine en_US
dc.subject Induced fit docking en_US
dc.subject Molecular dynamics en_US
dc.title 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 en_US
dc.type Article en_US
dc.description.pages 84-107 en_US
dc.description.note ©: The Authors. en_US
dc.description.cluster Chemicals
dc.description.impactarea Pharmaceutical Technologies
dc.identifier.apacitation Van 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. <i>ARKIVOC, Part V</i>, http://hdl.handle.net/10204/11890 en_ZA
dc.identifier.chicagocitation Van 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." <i>ARKIVOC, Part V</i> (2020) http://hdl.handle.net/10204/11890 en_ZA
dc.identifier.vancouvercitation Van 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. en_ZA
dc.identifier.ris 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 - en_ZA
dc.identifier.worklist 24362 en_US


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