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Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation

For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer’s disease and improve the pharmacokinetic properties of existing drugs. In the present study, we used three docking-based virtual screening...

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Autores principales: David, Benoit, Schneider, Pascal, Schäfer, Philipp, Pietruszka, Jörg, Gohlke, Holger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833026/
https://www.ncbi.nlm.nih.gov/pubmed/33478277
http://dx.doi.org/10.1080/14756366.2021.1876685
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author David, Benoit
Schneider, Pascal
Schäfer, Philipp
Pietruszka, Jörg
Gohlke, Holger
author_facet David, Benoit
Schneider, Pascal
Schäfer, Philipp
Pietruszka, Jörg
Gohlke, Holger
author_sort David, Benoit
collection PubMed
description For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer’s disease and improve the pharmacokinetic properties of existing drugs. In the present study, we used three docking-based virtual screening approaches to screen both ZINC15 and MolPort databases for synthetic analogs of physostigmine and donepezil, two highly potent AChE inhibitors. We characterised the in vitro inhibitory concentration of 11 compounds, ranging from 14 to 985 μM. The most potent of these compounds, S-I 26, showed a fivefold improved inhibitory concentration in comparison to rivastigmine. Moderate inhibitors carrying novel scaffolds were identified and could be improved for the development of new classes of AChE inhibitors.
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spelling pubmed-78330262021-02-02 Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation David, Benoit Schneider, Pascal Schäfer, Philipp Pietruszka, Jörg Gohlke, Holger J Enzyme Inhib Med Chem Research Paper For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer’s disease and improve the pharmacokinetic properties of existing drugs. In the present study, we used three docking-based virtual screening approaches to screen both ZINC15 and MolPort databases for synthetic analogs of physostigmine and donepezil, two highly potent AChE inhibitors. We characterised the in vitro inhibitory concentration of 11 compounds, ranging from 14 to 985 μM. The most potent of these compounds, S-I 26, showed a fivefold improved inhibitory concentration in comparison to rivastigmine. Moderate inhibitors carrying novel scaffolds were identified and could be improved for the development of new classes of AChE inhibitors. Taylor & Francis 2021-01-21 /pmc/articles/PMC7833026/ /pubmed/33478277 http://dx.doi.org/10.1080/14756366.2021.1876685 Text en © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
David, Benoit
Schneider, Pascal
Schäfer, Philipp
Pietruszka, Jörg
Gohlke, Holger
Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation
title Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation
title_full Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation
title_fullStr Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation
title_full_unstemmed Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation
title_short Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation
title_sort discovery of new acetylcholinesterase inhibitors for alzheimer’s disease: virtual screening and in vitro characterisation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833026/
https://www.ncbi.nlm.nih.gov/pubmed/33478277
http://dx.doi.org/10.1080/14756366.2021.1876685
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