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Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies.

Qiu JX, Zhou ZW, He ZX, Zhang X, Zhou SF, Zhu S - Drug Des Devel Ther (2015)

Bottom Line: The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes.The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans.Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response.

View Article: PubMed Central - PubMed

Affiliation: Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China ; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.

ABSTRACT
Ginger is one of the most commonly used herbal medicines for the treatment of numerous ailments and improvement of body functions. It may be used in combination with prescribed drugs. The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes. This study aimed to determine the molecular interactions between 12 main active ginger components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (-)-zingiberene, and methyl-6-isogingerol) and human cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the 12 ginger components using computational approaches and comprehensive literature search. Docking studies showed that ginger components interacted with a panel of amino acids in the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π-π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki ] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half-life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger-drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger-drug interactions.

No MeSH data available.


Related in: MedlinePlus

Binding modes of main active components of ginger in human CYP3A4 (PDB code 1W0F).Notes: Each compound–CYP3A4 complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected. (A) 6-Gingerol; (B) 8-gingerol; (C) 10-gingerol; (D) 6-shogaol; (E) 8-shogaol; (F) 10-shogaol; (G) ar-curcumene; (H) β-bisabolene; (I) β-sesquiphelandrene; (J) 6-gingerdione; (K) (−)-zingiberene; and (L) methyl-6-isogingerol.Abbreviation: CYP, cytochrome P450.
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f6-dddt-9-841: Binding modes of main active components of ginger in human CYP3A4 (PDB code 1W0F).Notes: Each compound–CYP3A4 complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected. (A) 6-Gingerol; (B) 8-gingerol; (C) 10-gingerol; (D) 6-shogaol; (E) 8-shogaol; (F) 10-shogaol; (G) ar-curcumene; (H) β-bisabolene; (I) β-sesquiphelandrene; (J) 6-gingerdione; (K) (−)-zingiberene; and (L) methyl-6-isogingerol.Abbreviation: CYP, cytochrome P450.

Mentions: First, we performed a computational docking study of 12 main active ginger components using Discovery Studio 3.1. Twelve ginger components including 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (−)-zingiberene, and methyl-6-isogingerol were docked into the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4, respectively. After docking the main active ginger components into the active sites of five human CYPs, 10 positions were generated for each compound–CYP interaction. The CDOCKER interaction energy ranged from 23.0 to 63.1 kcal/mol. Each compound–CYP complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected (Figures 2–6).


Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies.

Qiu JX, Zhou ZW, He ZX, Zhang X, Zhou SF, Zhu S - Drug Des Devel Ther (2015)

Binding modes of main active components of ginger in human CYP3A4 (PDB code 1W0F).Notes: Each compound–CYP3A4 complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected. (A) 6-Gingerol; (B) 8-gingerol; (C) 10-gingerol; (D) 6-shogaol; (E) 8-shogaol; (F) 10-shogaol; (G) ar-curcumene; (H) β-bisabolene; (I) β-sesquiphelandrene; (J) 6-gingerdione; (K) (−)-zingiberene; and (L) methyl-6-isogingerol.Abbreviation: CYP, cytochrome P450.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4338259&req=5

f6-dddt-9-841: Binding modes of main active components of ginger in human CYP3A4 (PDB code 1W0F).Notes: Each compound–CYP3A4 complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected. (A) 6-Gingerol; (B) 8-gingerol; (C) 10-gingerol; (D) 6-shogaol; (E) 8-shogaol; (F) 10-shogaol; (G) ar-curcumene; (H) β-bisabolene; (I) β-sesquiphelandrene; (J) 6-gingerdione; (K) (−)-zingiberene; and (L) methyl-6-isogingerol.Abbreviation: CYP, cytochrome P450.
Mentions: First, we performed a computational docking study of 12 main active ginger components using Discovery Studio 3.1. Twelve ginger components including 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (−)-zingiberene, and methyl-6-isogingerol were docked into the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4, respectively. After docking the main active ginger components into the active sites of five human CYPs, 10 positions were generated for each compound–CYP interaction. The CDOCKER interaction energy ranged from 23.0 to 63.1 kcal/mol. Each compound–CYP complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected (Figures 2–6).

Bottom Line: The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes.The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans.Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response.

View Article: PubMed Central - PubMed

Affiliation: Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China ; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.

ABSTRACT
Ginger is one of the most commonly used herbal medicines for the treatment of numerous ailments and improvement of body functions. It may be used in combination with prescribed drugs. The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes. This study aimed to determine the molecular interactions between 12 main active ginger components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (-)-zingiberene, and methyl-6-isogingerol) and human cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the 12 ginger components using computational approaches and comprehensive literature search. Docking studies showed that ginger components interacted with a panel of amino acids in the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π-π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki ] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half-life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger-drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger-drug interactions.

No MeSH data available.


Related in: MedlinePlus