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Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg

Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have been attracted as candidate treatments for Alzheimer's disease (AD). Fifteen khellactone-type coumarins from the roots of Peucedanum japonicum Thunberg were tested for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and...

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Autores principales: Heo, Jeong Hyun, Eom, Bo Hyun, Ryu, Hyung Won, Kang, Myung-Gyun, Park, Jong Eun, Kim, Doo-Young, Kim, Jung-Hee, Park, Daeui, Oh, Sei-Ryang, Kim, Hoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730441/
https://www.ncbi.nlm.nih.gov/pubmed/33303801
http://dx.doi.org/10.1038/s41598-020-78782-5
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author Heo, Jeong Hyun
Eom, Bo Hyun
Ryu, Hyung Won
Kang, Myung-Gyun
Park, Jong Eun
Kim, Doo-Young
Kim, Jung-Hee
Park, Daeui
Oh, Sei-Ryang
Kim, Hoon
author_facet Heo, Jeong Hyun
Eom, Bo Hyun
Ryu, Hyung Won
Kang, Myung-Gyun
Park, Jong Eun
Kim, Doo-Young
Kim, Jung-Hee
Park, Daeui
Oh, Sei-Ryang
Kim, Hoon
author_sort Heo, Jeong Hyun
collection PubMed
description Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have been attracted as candidate treatments for Alzheimer's disease (AD). Fifteen khellactone-type coumarins from the roots of Peucedanum japonicum Thunberg were tested for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and MAO inhibitory activities. Compound 3′-angeloyl-4′-(2-methylbutyryl)khellactone (PJ13) most potently inhibited AChE (IC(50) = 9.28 µM), followed by 3′-isovaleryl-4′-(2-methylbutyroyl)khellactone (PJ15) (IC(50) = 10.0 μM). Compound senecioyl-4′-angeloyl-khellactone (PJ5) most potently inhibited BChE (IC(50) = 7.22 μM) and had the highest selectivity index (> 5.54), followed by 3′-senecioyl-4′-(2-methylbutyryl)khellactone (PJ10) and 3′,4′-disenecioylkhellactone (PJ4) (IC(50) = 10.2 and 10.7 μM, respectively). Compounds PJ13, PJ15, and PJ5 showed reversible and mixed-types of inhibition with K(i) values of 5.98, 10.4 (for AChE), and 4.16 µM (for BChE), respectively. However, all 15 compounds weakly inhibited MAO-A and MAO-B. Molecular docking simulation revealed that PJ13 had a higher binding affinity (− 9.3 kcal/mol) with AChE than PJ15 (− 7.8 kcal/mol) or PJ5 (− 5.4 kcal/mol), due to the formation of a hydrogen bond with Tyr121 (distance: 2.52 Å). On the other hand, the binding affinity of PJ5 (− 10.0 kcal/mol) with BChE was higher than for PJ13 (− 7.7 kcal/mol) or PJ15 (− 8.1 kcal/mol), due to the formation of a hydrogen bond with Ser198 (distance: 2.05 Å). These results suggest that PJ13 and PJ5 are potential reversible selective inhibitors of AChE and BChE, respectively, for the treatment of AD.
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spelling pubmed-77304412020-12-14 Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg Heo, Jeong Hyun Eom, Bo Hyun Ryu, Hyung Won Kang, Myung-Gyun Park, Jong Eun Kim, Doo-Young Kim, Jung-Hee Park, Daeui Oh, Sei-Ryang Kim, Hoon Sci Rep Article Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have been attracted as candidate treatments for Alzheimer's disease (AD). Fifteen khellactone-type coumarins from the roots of Peucedanum japonicum Thunberg were tested for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and MAO inhibitory activities. Compound 3′-angeloyl-4′-(2-methylbutyryl)khellactone (PJ13) most potently inhibited AChE (IC(50) = 9.28 µM), followed by 3′-isovaleryl-4′-(2-methylbutyroyl)khellactone (PJ15) (IC(50) = 10.0 μM). Compound senecioyl-4′-angeloyl-khellactone (PJ5) most potently inhibited BChE (IC(50) = 7.22 μM) and had the highest selectivity index (> 5.54), followed by 3′-senecioyl-4′-(2-methylbutyryl)khellactone (PJ10) and 3′,4′-disenecioylkhellactone (PJ4) (IC(50) = 10.2 and 10.7 μM, respectively). Compounds PJ13, PJ15, and PJ5 showed reversible and mixed-types of inhibition with K(i) values of 5.98, 10.4 (for AChE), and 4.16 µM (for BChE), respectively. However, all 15 compounds weakly inhibited MAO-A and MAO-B. Molecular docking simulation revealed that PJ13 had a higher binding affinity (− 9.3 kcal/mol) with AChE than PJ15 (− 7.8 kcal/mol) or PJ5 (− 5.4 kcal/mol), due to the formation of a hydrogen bond with Tyr121 (distance: 2.52 Å). On the other hand, the binding affinity of PJ5 (− 10.0 kcal/mol) with BChE was higher than for PJ13 (− 7.7 kcal/mol) or PJ15 (− 8.1 kcal/mol), due to the formation of a hydrogen bond with Ser198 (distance: 2.05 Å). These results suggest that PJ13 and PJ5 are potential reversible selective inhibitors of AChE and BChE, respectively, for the treatment of AD. Nature Publishing Group UK 2020-12-10 /pmc/articles/PMC7730441/ /pubmed/33303801 http://dx.doi.org/10.1038/s41598-020-78782-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Heo, Jeong Hyun
Eom, Bo Hyun
Ryu, Hyung Won
Kang, Myung-Gyun
Park, Jong Eun
Kim, Doo-Young
Kim, Jung-Hee
Park, Daeui
Oh, Sei-Ryang
Kim, Hoon
Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg
title Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg
title_full Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg
title_fullStr Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg
title_full_unstemmed Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg
title_short Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg
title_sort acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from peucedanum japonicum thurnberg
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730441/
https://www.ncbi.nlm.nih.gov/pubmed/33303801
http://dx.doi.org/10.1038/s41598-020-78782-5
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