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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
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. |
format | Online Article Text |
id | pubmed-7730441 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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