Characterization of Dicaffeoylspermidine Derivatives from Wolfberry as Potent and Selective Inhibitors of Human Cytochrome P450 46A1 In vitro
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
BACKGROUND: Cytochrome P450 (CYP) 46A1 enzyme is a neuro-specific metabolic enzyme that converts cholesterol to 24-hydroxycholesterol. Inhibition of CYP46A1 activity is of great significance to improve neurodegenerative disorder.
OBJECTIVE: The present study aimed to investigate the inhibitory effect of wolfberry dicaffeoylspermidine derivatives on CYP46A1.
METHODS: The inhibitory effect of six wolfberry dicaffeoylspermidine derivatives on CYP46A1 activity was investigated using cholesterol as a substrate in vitro. Molecular docking was used to simulate the interactions between wolfberry dicaffeoylspermidine derivatives and CYP46A1.
RESULTS: Of these spermidines, lycibarbarspermidines D (1) and A (2) showed highly-selective and strong inhibitory effects on CYP46A1 but not on other human CYP isoforms. Both 1 and 2 exhibit mixed partial competitive inhibition of CYP46A1, with Ki values of 106 nM and 258 nM, respectively. Notably, 1 and 2 had excellent orientations within the active cavity of CYP46A1, and both formed three water-hydrogen bonds with W732 and W765, located near the heme of CYP46A1.
CONCLUSION: Compounds 1 and 2 showed a highly-selective and nanomolar affinity for CYP46A1 in vitro. These findings suggested that compounds 1 and 2 could be used as potent inhibitors of CYP46A1 in vitro.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Current drug metabolism - 24(2023), 2 vom: 07., Seite 124-130 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Du, Jie [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.06.2023 Date Revised 01.06.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.2174/1389200224666230207092813 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM352587695 |
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| 245 | 1 | 0 | |a Characterization of Dicaffeoylspermidine Derivatives from Wolfberry as Potent and Selective Inhibitors of Human Cytochrome P450 46A1 In vitro |
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| 500 | |a Date Revised 01.06.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a BACKGROUND: Cytochrome P450 (CYP) 46A1 enzyme is a neuro-specific metabolic enzyme that converts cholesterol to 24-hydroxycholesterol. Inhibition of CYP46A1 activity is of great significance to improve neurodegenerative disorder | ||
| 520 | |a OBJECTIVE: The present study aimed to investigate the inhibitory effect of wolfberry dicaffeoylspermidine derivatives on CYP46A1 | ||
| 520 | |a METHODS: The inhibitory effect of six wolfberry dicaffeoylspermidine derivatives on CYP46A1 activity was investigated using cholesterol as a substrate in vitro. Molecular docking was used to simulate the interactions between wolfberry dicaffeoylspermidine derivatives and CYP46A1 | ||
| 520 | |a RESULTS: Of these spermidines, lycibarbarspermidines D (1) and A (2) showed highly-selective and strong inhibitory effects on CYP46A1 but not on other human CYP isoforms. Both 1 and 2 exhibit mixed partial competitive inhibition of CYP46A1, with Ki values of 106 nM and 258 nM, respectively. Notably, 1 and 2 had excellent orientations within the active cavity of CYP46A1, and both formed three water-hydrogen bonds with W732 and W765, located near the heme of CYP46A1 | ||
| 520 | |a CONCLUSION: Compounds 1 and 2 showed a highly-selective and nanomolar affinity for CYP46A1 in vitro. These findings suggested that compounds 1 and 2 could be used as potent inhibitors of CYP46A1 in vitro | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Wolfberry | |
| 650 | 4 | |a dicaffeoylspermidine | |
| 650 | 4 | |a high selectivity | |
| 650 | 4 | |a molecular docking | |
| 650 | 4 | |a structure-inhibition relationship | |
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| 700 | 1 | |a Liu, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shujuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Changyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Huijun |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Kexin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jingjing |e verfasserin |4 aut | |
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