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Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations

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dc.contributor.author Van van der Westhuizen, Johan C
dc.contributor.author Stander, A
dc.contributor.author Riley, DL
dc.contributor.author Panayides, Jenny-Lee
dc.date.accessioned 2023-05-12T11:22:40Z
dc.date.available 2023-05-12T11:22:40Z
dc.date.issued 2022-03
dc.identifier.citation Van van der Westhuizen, J.C., Stander, A., Riley, D. & Panayides, J. 2022. Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations. <i>Journal of Chemical Information and Modeling, 62(6).</i> http://hdl.handle.net/10204/12776 en_ZA
dc.identifier.issn 1549-9596
dc.identifier.issn 1549-960X
dc.identifier.uri DOI: 10.1021/acs.jcim.1c01443
dc.identifier.uri http://hdl.handle.net/10204/12776
dc.description.abstract Alzheimer's disease is the most common neurodegenerative disease and currently poses a significant socioeconomic problem. This study describes the uses of computer-aided drug discovery techniques to identify novel inhibitors of acetylcholinesterase, a target for Alzheimer's disease. High-throughput virtual screening was employed to predict potential inhibitors of acetylcholinesterase. Validation of enrichment was performed with the DUD-E data set, showing that an ensemble of binding pocket conformations is critical when a diverse set of ligands are being screened. A total of 720 compounds were submitted for in vitro screening, which led to 25 hits being identified with IC50 values of less than 50 µM. The majority of these hits belonged to two scaffolds: 1-ethyl-3-methoxy-3-methylpyrrolidine and 1H-pyrrolo[3,2-c]pyridin-6-amine both of which are noted to be promising compounds for further optimization. As various possible binding poses were suggested from molecular docking, molecular dynamics simulations were employed to validate the poses. In the case of the most active compounds identified, a critical, stable water bridge formed deep within the binding pocket was identified potentially explaining in part the lack of activity for subsets of compounds that are not able to form this water bridge. en_US
dc.format Abstract en_US
dc.language.iso en en_US
dc.relation.uri https://pubmed.ncbi.nlm.nih.gov/35139637/ en_US
dc.relation.uri https://pubs.acs.org/doi/10.1021/acs.jcim.1c01443 en_US
dc.source Journal of Chemical Information and Modeling, 62(6) en_US
dc.subject Alzheimer's disease en_US
dc.subject Acetylcholinesterase inhibitors en_US
dc.subject In vitro screening en_US
dc.subject Neurodegenerative diseases en_US
dc.title Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations en_US
dc.type Article en_US
dc.description.pages 1550-1572 en_US
dc.description.note © 2022 American Chemical Society. Due to copyright restrictions, the attached PDF file only contains the abstract of the full text item. For access to the full text item, please consult the publisher's website: https://pubs.acs.org/doi/10.1021/acs.jcim.1c01443 en_US
dc.description.cluster Chemicals en_US
dc.description.impactarea Pharmaceutical Technologies en_US
dc.identifier.apacitation Van van der Westhuizen, J. C., Stander, A., Riley, D., & Panayides, J. (2022). Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations. <i>Journal of Chemical Information and Modeling, 62(6)</i>, http://hdl.handle.net/10204/12776 en_ZA
dc.identifier.chicagocitation Van van der Westhuizen, Johan C, A Stander, DL Riley, and Jenny-Lee Panayides "Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations." <i>Journal of Chemical Information and Modeling, 62(6)</i> (2022) http://hdl.handle.net/10204/12776 en_ZA
dc.identifier.vancouvercitation Van van der Westhuizen JC, Stander A, Riley D, Panayides J. Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations. Journal of Chemical Information and Modeling, 62(6). 2022; http://hdl.handle.net/10204/12776. en_ZA
dc.identifier.ris TY - Article AU - Van van der Westhuizen, Johan C AU - Stander, A AU - Riley, DL AU - Panayides, Jenny-Lee AB - Alzheimer's disease is the most common neurodegenerative disease and currently poses a significant socioeconomic problem. This study describes the uses of computer-aided drug discovery techniques to identify novel inhibitors of acetylcholinesterase, a target for Alzheimer's disease. High-throughput virtual screening was employed to predict potential inhibitors of acetylcholinesterase. Validation of enrichment was performed with the DUD-E data set, showing that an ensemble of binding pocket conformations is critical when a diverse set of ligands are being screened. A total of 720 compounds were submitted for in vitro screening, which led to 25 hits being identified with IC50 values of less than 50 µM. The majority of these hits belonged to two scaffolds: 1-ethyl-3-methoxy-3-methylpyrrolidine and 1H-pyrrolo[3,2-c]pyridin-6-amine both of which are noted to be promising compounds for further optimization. As various possible binding poses were suggested from molecular docking, molecular dynamics simulations were employed to validate the poses. In the case of the most active compounds identified, a critical, stable water bridge formed deep within the binding pocket was identified potentially explaining in part the lack of activity for subsets of compounds that are not able to form this water bridge. DA - 2022-03 DB - ResearchSpace DP - CSIR J1 - Journal of Chemical Information and Modeling, 62(6) KW - Alzheimer's disease KW - Acetylcholinesterase inhibitors KW - In vitro screening KW - Neurodegenerative diseases LK - https://researchspace.csir.co.za PY - 2022 SM - 1549-9596 SM - 1549-960X T1 - Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations TI - Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations UR - http://hdl.handle.net/10204/12776 ER - en_ZA
dc.identifier.worklist 26583 en_US


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