Open Access

A molecular docking study of phytochemical estrogen mimics from dietary herbal supplements

In Silico Pharmacology20153:4

DOI: 10.1186/s40203-015-0008-z

Received: 26 January 2015

Accepted: 10 March 2015

Published: 22 March 2015

Abstract

Purpose

The purpose of this study is to use a molecular docking approach to identify potential estrogen mimics or anti-estrogens in phytochemicals found in popular dietary herbal supplements.

Methods

In this study, 568 phytochemicals found in 17 of the most popular herbal supplements sold in the United States were built and docked with two isoforms of the estrogen receptor, ERα and ERβ (a total of 27 different protein crystal structures).

Results

The docking results revealed six strongly docking compounds in Echinacea, three from milk thistle (Silybum marianum), three from Gingko biloba, one from Sambucus nigra, none from maca (Lepidium meyenii), five from chaste tree (Vitex agnus-castus), two from fenugreek (Trigonella foenum-graecum), and two from Rhodiola rosea. Notably, of the most popular herbal supplements for women, there were numerous compounds that docked strongly with the estrogen receptor: Licorice (Glycyrrhiza glabra) had a total of 26 compounds strongly docking to the estrogen receptor, 15 with wild yam (Dioscorea villosa), 11 from black cohosh (Actaea racemosa), eight from muira puama (Ptychopetalum olacoides or P. uncinatum), eight from red clover (Trifolium pratense), three from damiana (Turnera aphrodisiaca or T. diffusa), and three from dong quai (Angelica sinensis). Of possible concern were the compounds from men’s herbal supplements that exhibited strong docking to the estrogen receptor: Gingko biloba had three compounds, gotu kola (Centella asiatica) had two, muira puama (Ptychopetalum olacoides or P. uncinatum) had eight, and Tribulus terrestris had six compounds.

Conclusions

This molecular docking study has revealed that almost all popular herbal supplements contain phytochemical components that may bind to the human estrogen receptor and exhibit selective estrogen receptor modulation. As such, these herbal supplements may cause unwanted side effects related to estrogenic activity.

Keywords

Molecular docking Estrogen receptor Herbal supplements

Background

The use of alternative medicines in the United States, particularly herbal supplements, has dramatically increased since the beginning of the 21st century (Figure 1). Filling American minds with promises of enhanced beauty, sharper senses, and optimum organ functions, herbal supplements claim to increase, or improve almost all issues a person could have with their body. Without a doubt it is appealing to have problems solved by simply swallowing a pill or drinking a tea, not much effort required, however it has been widely ignored the consecutive consequences these supplements can provide (Cupp 1999).
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Figure 1

Relationship between herbal supplement purchases in the United States and the year.

Two major factors play a part in the ongoing, unnoticed herbal supplement crisis: Regulations for herbal supplements and uneducated consumers. Beginning with the first, the United States does not classify herbal supplements as drugs, and therefore supplements are not required to undergo the extensive testing that pharmaceutical drugs do before put on the market. Courtesy of the “Dietary Supplement Health and Education Act of 1994”, herbal supplements are not evaluated by the Food and Drug Administration (Calixto 2000) making it easy for supplement companies to rapidly introduce new supplements to consumers, with or without the knowledge of possible harmful side effects. Unspecified drugs, contaminations, toxins, and/or heavy metals (Au et al. 2000) can be included in an herbal supplement, and since companies are not required to subject their products to quality analysis, this spectrum of harmful compounds could be digested by a consumer and induce adverse effects. As for the second, biologically uneducated consumers do not understand or simply do not consider the concept that plants are not always beneficial. They believe anything that is natural must be good for their health and safe to consume (Stonemetz 2008), which is far from the truth. Plants contain hundreds of phytochemicals, some of which are indeed toxic to the human body. One class of phytochemicals of major concern, which is the focus of this study, phytoestrogens, can interfere and react with the human estrogen receptors, which regulate neural, skeletal, cardiovascular, and reproductive tissues. This interference, however, is not always adverse. For example, some phytoestrogens can promote carcinogenic growth, while others can inhibit the growth.

The purpose of this study was to identify potential estrogen mimics or anti-estrogens in phytochemicals found in popular dietary herbal supplements. The data gathered can only suggest the possibility of a phytochemical to be an anti-estrogen or a mimic, not confirm its estrogenic properties. It is our hope that the discoveries made during this study can help to identify the estrogenic activity of the phytochemicals examined. This information can then lead to the health benefits or hazards associated with the phytochemicals, which in turn could greatly affect the increasingly popular herbal supplement movement.

Methods

Literature survey

A literature survey on herbal supplements was carried out to identify the most popular general [Echinacea, milk thistle (Silybum marianum), Ginkgo biloba, Sambucus nigra, maca (Lepidium meyenii), chaste tree (Vitex agnus-castus), fenugreek (Trigonella foenum-graecum), and Rhodiola rosea], women’s [damiana leaf (Turnera aphrodisiaca, T. diffusa), muira puama (Ptychopetalum olacoides, P. uncinatum), black cohosh (Actaea racemosa = Cimifuga racemosa), licorice root (Glycyrrhiza glabra), wild yam (Dioscorea villosa), dong quai (Angelica sinensis) and red clover (Trifolium pretense)], and men’s [Gingko biloba, gotu kola (Centella asiatica), muira puama (Ptychopetalum olacoides, P. uncinatum), and Tribulus terrestris] herbal supplements advertised and used in the United States. A survey of the literature, including the Dictionary of Natural Products (2014) and Duke’s Phytochemical Database (1998), was carried out to determine the phytochemical constituents of each herb.

Molecular modeling of phytochemicals

Each phytochemical ligand structure (see Figures 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, and 43) was built using Spartan ’14 for Windows (2013). For each ligand, a conformational search and geometry optimization was carried out using the MMFF force field (Halgren 1996).
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Figure 2

Alkaloid ligands examined in this work.

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Figure 3

Chalcone ligands examined in this work.

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Figure 4

Coumarin ligands examined in this work.

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Figure 5

Additional coumarin ligands examined in this work.

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Figure 6

Diterpenoid ligands examined in this work.

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Figure 7

Additional diterpenoid ligands examined in this work.

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Figure 8

Additional diterpenoid ligands examined in this work.

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Figure 9

Additional diterpenoid ligands examined in this work.

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Figure 10

Flavonoid ligands examined in this work.

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Figure 11

Additional flavonoid ligands examined in this work.

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Figure 12

Additional flavonoid ligands examined in this work.

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Figure 13

Additional flavonoid ligands examined in this work.

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Figure 14

Additional flavonoid ligands examined in this work.

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Figure 15

Additional flavonoid ligands examined in this work.

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Figure 16

Additional flavonoid ligands examined in this work.

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Figure 17

Additional flavonoid ligands examined in this work.

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Figure 18

Isoflavonoid ligands examined in this work.

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Figure 19

Additional isoflavonoid ligands examined in this work.

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Figure 20

Additional isoflavonoid ligands examined in this work.

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Figure 21

Lignan ligands examined in this work.

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Figure 22

Phenanthrenoid ligands examined in this work.

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Figure 23

Miscellaneous phenolic compounds examined in this work.

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Figure 24

Additional miscellaneous phenolic compounds examined in this work.

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Figure 25

Additional miscellaneous phenolic compounds examined in this work.

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Figure 26

Sesquiterpenoid ligands examined in this work.

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Figure 27

Steroid ligands examined in this work.

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Figure 28

Additional steroid ligands examined in this work.

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Figure 29

Additional steroid ligands examined in this work.

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Figure 30

Additional steroid ligands examined in this work.

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Figure 31

Additional steroid ligands examined in this work.

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Figure 32

Additional steroid ligands examined in this work.

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Figure 33

Additional steroid ligands examined in this work.

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Figure 34

Additional steroid ligands examined in this work.

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Figure 35

Stilbenoid ligands examined in this work.

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Figure 36

Additional stilbenoid ligands examined in this work.

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Figure 37

Triterpenoid ligands examined in this work.

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Figure 38

Additional triterpenoid ligands examined in this work.

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Figure 39

Additional triterpenoid ligands examined in this work.

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Figure 40

Additional triterpenoid ligands examined in this work.

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Figure 41

Additional triterpenoid ligands examined in this work.

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Figure 42

Miscellaneous phytochemical ligands examined in this work.

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Figure 43

Additional miscellaneous phytochemical ligands examined in this work.

Molecular docking

Protein-ligand docking studies were carried out based on the crystal structures of human estrogen receptor α [ERα: PDB 1X7E (Manas et al. 2004a), PDB 1X7R (Manas et al. 2004b), and PDB 3ERD (Shiau et al. 1998)] and human estrogen receptor β [ERβ: PDB 1U3Q, 1U3R, 1U3S (Malamas et al. 2004), 1U9E, 1X7B, 1X76, 1X78 (Manas et al. 2004a), and 1X7J (Manas et al. 2004b)]. Prior to docking all solvent molecules and the co-crystallized ligands were removed from the structures. Molecular docking calculations for all compounds with each of the proteins were undertaken using Molegro Virtual Docker v. 6.0 (2013). Potential binding sites in the protein structures were identified using the grid-based cavity prediction algorithm of the Molegro Virtual Docker (2013) program. The location of the volume used by the docking search algorithm was positioned at the center of the cavity and a sphere (15 Å radius) large enough to encompass the entire cavity of the binding site of each protein structure was selected in order to allow each ligand to search. If a co-crystallized inhibitor or substrate was present in the structure, then that site was chosen as the binding site. If no co-crystallized ligand was present, then suitably sized (>50 Å3) cavities were used as potential binding sites. The docking searches were constrained to those cavities. Standard protonation states of the proteins based on neutral pH were used in the docking studies. Each protein was used as a rigid model structure; no relaxation of the protein was performed. Assignments of charges on each protein were based on standard templates as part of the Molegro Virtual Docker (2013) program (Thomsen and Christensen 2006); no other charges were necessary to be set. Flexible ligand models were used in the docking and subsequent optimization scheme. As a test of docking accuracy and for docking energy comparison, co-crystallized ligands were re-docked into the protein structures (see Table 1). Additionally, as positive controls, the known estrogenic compounds 17β-estradiol and α-zearalenone were docked with each protein structure in order to compare docking energies with the herbal phytochemicals. Different orientations of the ligands were searched and ranked based on their energy scores. The RMSD threshold for multiple cluster poses was set at <1.00 Å. The docking algorithm was set at maximum iterations of 1500 with a simplex evolution population size of 50 and a minimum of 30 runs for each ligand. Each binding site of oligomeric structures was searched with each ligand. The lowest-energy (strongest-docking) poses for each ligand in each protein target are summarized in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
Table 1

MolDock docking energies of co-crystallized ligands and root-mean-squared deviations between the co-crystallized ligand and the re-docked poses of the co-crystallized ligand with human estrogen receptors α and β

Protein

PDB code

Co-crystallized ligand

E dock (kJ/mol)

RMSD (Å)

ERα

1X7E

[5-hydroxy-2-(4-hydroxyphenyl)-1-benzofuran-7-yx]acetonitrile

−100.9

0.46

 

1X7R

genistein

−95.3

0.44

 

3ERD

diethylstilbestrol

−97.0

0.75

ERβ

1U3Q

4-(6-hydroxybenzo[d]isoxazol-3-yl)benzene-1,3-diol

−98.9

1.40

 

1U3R

2-(5-hydroxynaphthalen-1-yl)-1,3-benzooxazol-6-ol

−111.3

0.36

 

1U3S

3-(6-hydroxynaphthalen-2-yl)-benzo[d]isoxazol-6-ol

−107.7

0.35

 

1U9E

2-(4-hydroxyphenyl)benzofuran-5-ol

−90.4

0.62

 

1X7B

2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol

−107.9

0.46

 

1X7J

genistein

−99.9

0.66

 

1X76

5-hydroxy-2-(4-hydroxyphenyl)-1-benzofuran-7-carbonitrile

−101.3

0.42

 

1X78

[5-hydroxy-2-(4-hydroxyphenyl)-1-benzofuran-7-yl]carbonitrile

−107.7

0.40

Table 2

MolDock molecular docking energies (kJ/mol) for alkaloids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

cimitrypazepine

Cimicifuga racemosa

−87.6

−75.5

cis-clovamide

Trifolium pratense

−119.8

−124.9

trans-clovamide

Trifolium pratense

−113.6

−122.0

dihydrodioscorine

Dioscorea spp.

−60.2

−64.9

dioscoretine

Dioscorea spp.

−81.8

−80.9

dioscorine

Dioscorea spp.

−62.1

−68.1

dopargine

Cimicifuga racemosa

−97.9

−100.6

dumetorine

Dioscorea spp.

−77.0

−82.3

N-trans-feruloyltyramine

Tribulus terrestris

−103.1

−113.8

gentianine

Trigonella foenum-graecum

−67.2

−64.9

harman

Tribulus terrestris

−74.9

−67.4

harmine

Tribulus terrestris

−68.8

−78.0

harmol

Tribulus terrestris

−85.8

−75.5

lepidiline A

Lepidium meyenii

−91.2

−96.9

macaridine

Lepidium meyenii

−78.0

−78.2

perlolyrine

Tribulus terrestris

−93.4

−104.6

terresoxazine

Tribulus terrestris

−66.3

−74.7

terrestribisamide

Tribulus terrestris

−102.1

−101.2

1,2,3,4-tetrahydro-6-hydroxy-2-methyl-β-carboline

Cimicifuga racemosa

−73.5

−78.2

Tribulusamide A

Tribulus terrestris

−48.7

no dock

Tribulusamide B

Tribulus terrestris

no dock

no dock

Table 3

MolDock molecular docking energies (kJ/mol) for chalcones with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

cordifolin

Glycyrrhiza glabra

−102.2

−110.2

1,2-dihydroparatocarpin A

Glycyrrhiza glabra

no dock

−11.2

4-hydroxychalcone

Glycyrrhiza glabra

−88.4

−94.5

isoliquiritigenin

Glycyrrhiza glabra

−99.9

−102.6

kanzonol Y

Glycyrrhiza glabra

−111.2

−122.4

licoagrochalcone A

Glycyrrhiza glabra

−102.4

−115.5

licoagrochalcone B

Glycyrrhiza glabra

−55.8

−112.0

licoagrochalcone C

Glycyrrhiza glabra

−90.7

−103.1

licoagrochalcone D

Glycyrrhiza glabra

−14.6

−100.5

licochalcone A

Glycyrrhiza glabra

−93.2

−107.8

licochalcone B

Glycyrrhiza glabra

−107.8

−108.9

α,2′,4,4′-tetrahydroxydihydrochalcone

Glycyrrhiza glabra

−98.3

−105.0

2,4,4′-trihydroxychalcone

Glycyrrhiza glabra

−103.4

−104.9

xanthohumol

Glycyrrhiza glabra

−116.8

−116.8

Table 4

MolDock molecular docking energies (kJ/mol) for coumarins with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

7-acetoxy-4-methylcoumarin

Trigonella foenum-graecum

−74.6

−77.6

bergapten

Glycyrrhiza glabra

−71.2

−77.6

coumestrol

Glycyrrhiza glabra

−89.4

−99.8

Trifolium pratense

3,4-didehydroglabridin

Glycyrrhiza glabra

−34.7

−90.0

6α,7-dihydroxymaackiain

Trifolium pratense

−97.7

−107.9

gancaonin F

Glycyrrhiza glabra

−37.5

−109.6

glabrene

Glycyrrhiza glabra

−104.8

−114.9

glabrocoumarin

Glycyrrhiza glabra

−99.0

−109.7

glycycoumarin

Glycyrrhiza glabra

−75.2

−110.2

glycyrol

Glycyrrhiza glabra

−49.2

−108.8

glyinflanin H

Glycyrrhiza glabra

−53.3

−102.1

hispaglabridin A

Glycyrrhiza glabra

−68.5

−84.3

hispaglabridin B

Glycyrrhiza glabra

−42.8

−59.3

6α-hydroxymaackiain

Trifolium pratense

−95.9

−102.9

3′-hydroxy-4′-methoxyglabridin

Glycyrrhiza glabra

−35.9

−86.9

isoglycycoumarin

Glycyrrhiza glabra

−20.3

−77.6

isoglycyrol

Glycyrrhiza glabra

−10.8

−66.1

kanzonol U

Glycyrrhiza glabra

−102.8

−109.9

kanzonol V

Glycyrrhiza glabra

−23.7

−71.3

kanzonol W

Glycyrrhiza glabra

−20.4

−82.5

licocoumarin A

Glycyrrhiza glabra

−54.9

−24.2

maackiain

Trifolium pratense

−84.3

−83.6

medicagol

Trifolium pratense

−91.6

−107.6

medicarpin

Trifolium pratense

−83.7

−79.1

9-O-methylcoumestrol

Trifolium pratense

−88.2

−100.8

2′-O-methylglabridin

Glycyrrhiza glabra

−78.7

−78.2

4′-O-methylgrabridin

Glycyrrhiza glabra

−25.4

−80.8

4′-O-methylkanzonol W

Glycyrrhiza glabra

no dock

−69.4

mirificoumestan

Pueraria mirifica

−98.9

−113.0

pisatin

Trifolium pratense

−84.7

−96.8

pratenol A

Trifolium pratense

−93.7

−99.4

pratenol B

Trifolium pratense

−104.8

−112.0

trifolian

Trifolium pratense

−82.0

−71.9

trigocoumarin

Trigonella foenum-graecum

−93.6

−98.1

trigoforin

Trigonella foenum-graecum

−59.0

−66.2

variabilin

Trifolium pratense

−86.5

−86.9

Table 5

MolDock molecular docking energies (kJ/mol) for diterpenoids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

antadiosbulbin A

Dioscorea spp.

−102.7

−68.7

antadiosbulbin B

Dioscorea spp.

−76.0

−64.9

bafoudiosbulbin A

Dioscorea spp.

−102.2

−79.3

bafoudiosbulbin B

Dioscorea spp.

−95.6

−98.9

bafoudiosbulbin C

Dioscorea spp.

−68.0

−93.1

bafoudiosbulbin D

Dioscorea spp.

−79.3

−75.8

bafoudiosbulbin E

Dioscorea spp.

−84.1

−62.2

bafoudiosbulbin F

Dioscorea spp.

−86.0

−73.6

bafoudiosbulbin_G

Dioscorea spp.

−56.3

−13.0

6α,7α-dihydroxyannonene

Ptychopetalum olacoides, P. uncinatum

−95.2

−107.3

7,20-dihydroxyannonene

Ptychopetalum olacoides, P. uncinatum

−91.8

−105.5

6,7-dihydroxykolavenol

Ptychopetalum olacoides, P. uncinatum

−94.0

−107.0

diosbulbin A

Dioscorea spp.

−82.3

−47.7

diosbulbin B

Dioscorea spp.

−86.7

−81.8

diosbulbin C

Dioscorea spp.

−83.9

−50.1

diosbulbin D

Dioscorea spp.

−107.1

−110.4

diosbulbin E

Dioscorea spp.

−92.2

−108.1

diosbulbin F

Dioscorea spp.

−111.2

−114.8

diosbulbin G

Dioscorea spp.

−89.9

−72.0

diosbulbin H

Dioscorea spp.

−97.5

−114.1

diosbulbin I

Dioscorea spp.

no dock

no dock

diosbulbin J

Dioscorea spp.

−106.4

−107.1

diosbulbin K

Dioscorea spp.

−112.1

−108.3

diosbulbin L

Dioscorea spp.

−110.8

−110.9

diosbulbin M

Dioscorea spp.

−103.1

−107.8

8-epidiosbulbin E

Dioscorea spp.

−78.3

−72.8

8-epidiosbulbin E acetate

Dioscorea spp.

−16.8

−35.0

8-epidiosbulbin G

Dioscorea spp.

−89.3

−72.8

15,16-epoxy-6,8-dihydroxy-19-nor-13(16),14-clerodadiene-17,12:18,2-diolide-6-acetate

Dioscorea spp.

−38.1

−26.8

7-hydroxykolavelool

Ptychopetalum olacoides, P. uncinatum

−90.7

−100.1

7-hydroxysolidagolactone

Ptychopetalum olacoides, P. uncinatum

−96.1

−109.4

kolavelool

Ptychopetalum olacoides, P. uncinatum

−89.4

−94.8

8,14-labdadiene-6,7,13-triol-6,7-diacetate

Vitex agnus-castus

−92.4

−90.7

20-O-methylptychonal acetal

Ptychopetalum olacoides, P. uncinatum

−92.6

−105.1

7-oxokolavelool

Ptychopetalum olacoides, P. uncinatum

−91.6

−99.7

ptycho-6α,7α-diol

Ptychopetalum olacoides, P. uncinatum

−103.6

−122.9

ptycholide I

Ptychopetalum olacoides, P. uncinatum

−101.0

−108.9

ptycholide II

Ptychopetalum olacoides, P. uncinatum

−105.1

−104.6

ptycholide III

Ptychopetalum olacoides, P. uncinatum

−98.6

−109.1

ptycholide IV

Ptychopetalum olacoides, P. uncinatum

−103.7

−114.7

ptychonal

Ptychopetalum olacoides, P. uncinatum

−93.8

−104.7

ptychonal (hemiacetal)

Ptychopetalum olacoides, P. uncinatum

−93.4

−105.9

ptychonolide

Ptychopetalum olacoides, P. uncinatum

−87.7

−99.9

viteagnuside A (aglycone)

Vitex agnus-castus

−100.1

−101.9

viteagnusin A

Vitex agnus-castus

−87.4

−94.6

viteagnusin_B

Vitex agnus-castus

−75.5

−95.6

viteagnusin D

Vitex agnus-castus

−92.4

−97.3

viteagnusin E

Vitex agnus-castus

−3.7

−37.0

viteagnusin F

Vitex agnus-castus

−7.1

no dock

viteagnusin G

Vitex agnus-castus

−44.3

−76.4

viteagnusin H

Vitex agnus-castus

−93.5

−94.3

viteagnusin I

Vitex agnus-castus

−44.2

−46.1

viteagnusin J

Vitex agnus-castus

−54.5

−93.5

vitexlactam A

Vitex agnus-castus

−102.4

−99.1

Table 6

MolDock molecular docking energies (kJ/mol) for flavonoids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

acacetin

Ginkgo biloba

−83.6

−96.0

Turnera aphrodisiaca

Turnera diffusa

amentoflavone

Ginkgo biloba

no dock

no dock

apigenin

Ginkgo biloba

−88.6

−97.3

Silybum marianum

Turnera aphrodisiaca

Turnera diffusa

Vitex agnus-castus

bilobetin

Ginkgo biloba

no dock

no dock

6"-caffeoylisoorientin

Vitex agnus-castus

no dock

no dock

6"-caffeoylisoorientin(4"-methylether)

Vitex agnus-castus

no dock

no dock

8-(5-carboxy-2-methoxyphenyl)-5,7-dihydroxy-4"-methoxyflavone

Ginkgo biloba

−50.1

−78.2

casticin

Centella asiatica

−15.6

−106.4

Vitex agnus-castus

castillicetin

Centella asiatica

−59.1

−89.5

castilliferol

Centella asiatica

−48.5

−85.2

chrysin

Ginkgo biloba

−81.6

−88.2

chrysoeriol

Silybum marianum

−94.6

−102.6

cisilandrin

Silybum marianum

no dock

no dock

2"-O-p-coumaroylorientin

Trigonella foenum-gracum

no dock

no dock

2"-O-p-coumaroylvitexin

Trigonella foenum-gracum

no dock

no dock

cyanidin

Ginkgo biloba

−89.1

−101.9

Trifolium pratense

2,3-dehydrosilybin

Silybum marianum

no dock

no dock

2,3-dehydrosilychristin

Silybum marianum

no dock

no dock

delphinidin

Trifolium pratense

−91.6

−102.3

5-O-demethyltangeretin

Vitex agnus-castus

−61.5

−101.1

6,8-digalactosylapigenin

Trigonella foenum-gracum

no dock

no dock

diosmetin

Turnera aphrodisiaca

−87.8

−102.0

Turnera diffusa

epigallocatechin

Ginkgo biloba

−88.1

−80.5

eriodictyol

Silybum marianum

−89.1

−101.3

folerogenin

Glycyrrhiza glabra

−78.2

−71.4

8-galactopyranosyl-6-quinovopyranosylapigenin

Trigonella foenum-graecum

no dock

no dock

8-galactopyranosyl-6-xylopyranosylapigenin

Trigonella foenum-graecum

no dock

no dock

garbanzol

Trifolium pratense

−84.7

−83.6

ginkgetin

Ginkgo biloba

no dock

no dock

glabranin

Glycyrrhiza glabra

−90.3

−94.3

glabrol

Glycyrrhiza glabra

−96.1

−97.4

gonzalitosin

Turnera aphrodisiaca

−71.7

−106.3

Turnera diffusa

gossypetin

Rhodiola rosea

−98.6

−105.7

(2R,3S,4S)-3,3′,4,4′,5,5′,7-heptahydroxyflavan

Ginkgo biloba

−89.9

−82.8

herbacetin

Rhodiola rosea

−94.6

−102.1

3-hydroxyglabrol

Glycyrrhiza glabra

−68.9

−101.5

isocisilandrin

Silybum marianum

no dock

no dock

isoginkgetin

Ginkgo biloba

no dock

no dock

isolicoflavonol

Glycyrrhiza glabra

−97.0

−102.0

isoorientin

Tribulus terrestris

no dock

no dock

Trigonella foenum-graecum

Vitex agnus-castus

isorhamnetin

Trifolium pratense

−95.2

−103.4

isoschaftoside

Glycyrrhiza glabra

no dock

no dock

isosilandrin A

Silybum marianum

no dock

no dock

isosilandrin B

Silybum marianum

no dock

no dock

isosilybin A

Silybum marianum

no dock

no dock

isosilybin B

Silybum marianum

no dock

no dock

isosilybin C

Silybum marianum

no dock

no dock

isosilybin D

Silybum marianum

no dock

no dock

isosilychristin

Silybum marianum

no dock

−69.6

isoviolanthin

Glycyrrhiza glabra

−44.1

no dock

isovitexin

Trigonella foenum-graecum

no dock

−6.7

Vitex agnus-castus

isoxanthohumol

Humulus lupulus

−102.5

−99.6

kaempferol

Ginkgo biloba

−90.1

−98.8

Glycyrrhiza glabra

Silybum marianum

Tribulus terrestris

Trifolium pretense

Trigonella foenum-graecum

kumatakenin

Glycyrrhiza glabra

−88.3

−101.2

laricitrin

Turnera aphrodisiaca

−90.4

−107.3

Turnera diffusa

licoagrodin

Glycyrrhiza glabra

no dock

no dock

licoflavanone

Glycyrrhiza glabra

−95.2

−102.2

liquiritigenin

Glycyrrhiza glabra

−84.9

−97.1

luteolin

Trigonella foenum-graecum

−92.0

−103.5

Vitex agnus-castus

luteolin-8-propenoic acid

Turnera aphrodisiaca

−113.1

−123.1

Turnera diffusa

malvidin

Trifolium pratense

−86.0

−99.9

5′-methoxybilobetin

Ginkgo biloba

no dock

no dock

myricetin

Trifolium pratense

−90.7

−106.2

naringenin

Glycyrrhiza glabra

−86.3

−95.4

Silybum marianum

neocorymboside

Trigonella foenum-graecum

no dock

no dock

neosilyhermin A

Silybum marianum

−42.8

−44.5

neosilyhermin B

Silybum marianum

no dock

−67.6

norwogonin

Glycyrrhiza glabra

−83.7

−91.9

orientin

Trigonella foenum-graecum

−83.7

−79.2

Turnera aphrodisiaca

Turnera diffusa

Vitex agnus-castus

orientin-3"-ketone

Turnera aphrodisiaca

−83.8

−74.3

Turnera diffusa

pectolinarigenin

Trifolium pratense

−84.8

−99.7

peonidin

Ginkgo biloba

−94.0

−100.5

Trifolium pratense

pinocembrin

Glycyrrhiza glabra

−81.4

−88.1

Turnera aphrodisiaca

Turnera diffusa

6-prenyleriodictyol

Glycyrrhiza glabra

−82.1

−91.2

8-prenyleriodictyol

Glycyrrhiza uralensis

−102.9

−87.7

6-prenylnaringenin

Glycyrrhiza glabra

−62.8

−91.7

8-prenylnaringenin

Humulus lupulus

−99.2

−102.8

6-prenylpinocembrin

Glycyrrhiza glabra

−49.1

−89.1

quercetin

Ginkgo biloba

−94.5

−106.0

Glycyrrhiza glabra

Sambucus nigra

Silybum marianum

Tribulus terrestris

Trigonella foenum-graecum

rhodiolin

Rhodiola rosea

no dock

no dock

santin

Vitex agnus-castus

−31.3

−107.9

sciadopitysin

Ginkgo biloba

no dock

no dock

shinflavanone

Glycyrrhiza glabra

−63.1

−77.4

sigmoidin B

Glycyrrhiza uralensis

−35.5

−92.7

silandrin A

Silybum marianum

no dock

no dock

silandrin B

Silybum marianum

no dock

no dock

silyamandin

Silybum marianum

no dock

no dock

silybin A

Silybum marianum

no dock

no dock

silybin B

Silybum marianum

no dock

no dock

silychristin

Silybum marianum

no dock

no dock

silychristin B

Silybum marianum

−69.2

no dock

silydianin

Silybum marianum

no dock

−73.5

silyhermin

Silybum marianum

no dock

72.2

silymonin

Silybum marianum

no dock

−69.2

syringetin

Turnera aphrodisiaca

−80.5

−95.1

Turnera diffusa

taxifolin

Silybum marianum

−89.4

−104.6

3,4′,5,8-tetrahydroxyflavone

Trifolium pratense

−92.0

−103.1

tricetin

Ginkgo biloba

−86.2

−106.2

trigraecum

Trigonella foenum-graecum

−82.7

−94.4

vicenin 1

Trigonella foenum-graecum

no dock

no dock

vicenin 2

Trigonella foenum-graecum

no dock

no dock

vicenin 3

Trigonella foenum-graecum

no dock

no dock

vitexin

Glycyrrhiza glabra

−83.7

−88.5

Vitex agnus-castus

Table 7

MolDock molecular docking energies (kJ/mol) for isoflavonoids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

7-acetoxy-2-methylisoflavone

Glycyrrhiza glabra

−78.4

−94.9

biochanin A

Trifolium pratense

−90.2

−98.6

calycosin

Trifolium pratense

−86.0

−103.3

daidzein

Trifolium pratense

−88.1

−95.0

formononetin

Cimicifuga racemosa

−83.5

−98.5

genistein

Glycyrrhiza glabra

−93.4

−98.9

Trifolium pratense

glabraisoflavanone A

Glycyrrhiza glabra

no dock

no dock

glabraisoflavanone B

Glycyrrhiza glabra

no dock

no dock

glabridin

Glycyrrhiza glabra

−15.8

−92.9

glabroisoflavanone A

Glycyrrhiza glabra

−35.5

−87.5

glabroisoflavanone B

Glycyrrhiza glabra

−29.1

−100.1

glabrone

Glycyrrhiza glabra

−39.0

−87.5

glyasperin B

Glycyrrhiza glabra

−81.7

−90.1

glyasperin K

Glycyrrhiza glabra

−35.4

−64.0

glyzaglabrin

Glycyrrhiza glabra

−99.1

−103.9

glyzarin

Glycyrrhiza glabra

−93.3

−94.2

7-hydroxy-2-methylisoflavone

Glycyrrhiza glabra

−79.0

−87.3

irilone

Trifolium pratense

−87.4

−102.8

isoderrone

Glycyrrhiza glabra

−27.5

−84.1

isoglabrone

Glycyrrhiza glabra

−34.1

−75.1

isomucronulatol

Glycyrrhiza glabra

−87.1

−104.4

kanzonol R

Glycyrrhiza glabra

−82.9

−101.7

kanzonol T

Glycyrrhiza glabra

no dock

no dock

kanzonol X

Glycyrrhiza glabra

−54.9

−51.2

licoagroside A (aglycone)

Glycyrrhiza glabra

−100.5

−107.7

licoricidin

Glycyrrhiza glabra

−41.5

no dock

lupiwighteone

Glycyrrhiza glabra

−96.1

−107.8

7-methoxy-2-methylisoflavone

Glycyrrhiza glabra

−79.2

−86.9

1-methoxyphaseollin

Glycyrrhiza glabra

−76.2

−110.5

phaseollinisoflavan

Glycyrrhiza glabra

−63.7

−89.4

pratensein

Trifolium pratense

−93.7

−106.4

8-prenylphaseollinisoflavan

Glycyrrhiza glabra

no dock

−43.2

prunetin

Glycyrrhiza glabra

−92.8

−98.9

pseudobaptigenin

Trifolium pratense

−94.6

−104.1

shinpterocarpin

Glycyrrhiza glabra

−65.3

−95.1

2′,4′,5,7-tetrahydroxy-3′,8-diprenylisoflavanone

Glycyrrhiza glabra

−37.0

−34.8

tetrapterol G

Glycyrrhiza glabra

−49.9

−100.8

3′,5,7-trihydroxy-5′-methoxyisoflavone

Trigonella foenum-graecum

−97.4

−107.9

wighteone

Glycyrrhiza glabra

−75.8

−101.9

vitexcarpan

Vitex agnus-castus

−70.4

−99.5

Table 8

MolDock molecular docking energies (kJ/mol) for lignans with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

actaealactone

Cimicifuga racemosa

−102.8

−112.3

(−)-arctigenin

Arctium lappa

−109.9

−116.2

(Z)-dehydrodiconiferyl alcohol

Silybum marianum

−97.9

−110.6

dihydrodehydrodiconiferyl alcohol (9-acetate)

Sambucus nigra

−102.7

−97.5

7′-hydroxymatairesinol

Podocarpus spicatus

−112.3

−117.3

isolariciresinol

Picea excelsa

−76.2

−84.6

(+)-lariciresinol

Rhodiola rosea

−104.2

−113.7

licoagrocarpin

Glycyrrhiza glabra

−90.4

−85.4

nordihydroguaiaretic acid

Guaiacum officinale

−102.1

−106.4

(−)-nortrachelogenin

Pinus palustris

−112.0

−125.4

pinoresinol

Picea excelsa

−106.4

−117.7

secoisolariciresinol

Picea abies

−109.1

−114.2

sesamin

Ginkgo biloba

−99.1

−121.8

Table 9

MolDock molecular docking energies (kJ/mol) for phenanthrenoids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

batatasin I

Dioscorea spp.

−84.7

−97.1

denthyrsinin

Dioscorea spp.

−83.5

−96.7

9,10-dihydro-2,7-dihydroxy-1,3,5-trimethoxyphenanthrene

Dioscorea spp.

−80.8

−95.7

9,10-dihydro-5,7-dimethoxy-3,4-phenanthrenediol

Dioscorea spp.

−81.0

−90.1

9,10-dihydro-2,3,5,7-phenanthrenetetrol

Dioscorea spp.

−78.0

−83.2

9,10-dihydro-4,6,7-trimethoxy-2-phenanthrenol

Dioscorea spp.

−88.5

−99.6

9,10-dihydro-5,6,8-trimethoxy-3,4-phenanthrenediol

Dioscorea spp.

−72.9

−87.5

6,7-dihydroxy-2-methoxy-1,4-phenanthraquinone

Dioscorea spp.

−85.9

−94.9

3,5-dimethoxy-2,7-phenanthrenediol

Dioscorea spp.

−84.6

−93.5

5,7-dimethoxy-2,3-phenanthrenediol

Dioscorea spp.

−88.5

−93.6

diobulbinone

Dioscorea spp.

no dock

no dock

dioscoreanone

Dioscorea spp.

−88.6

−96.1

hircinol

Dioscorea spp.

−68.9

−76.3

6-methoxycoelonin

Dioscorea spp.

−83.5

−93.9

2,4,5,6-phenanthrenetetrol

Dioscorea spp.

−74.7

−82.9

3,4,6-phenanthrenetriol

Dioscorea spp.

−74.3

−79.9

prazerol

Dioscorea spp.

−84.6

−96.5

Table 10

MolDock molecular docking energies (kJ/mol) for miscellaneous phenolic ligands with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

agnucastoside C (aglycone)

Vitex agnus-castus

−106.9

−130.0

agnuside (aglycone)

Vitex agnus-castus

−103.1

−110.3

angeliferulate

Angelica sinensis

−110.7

−121.5

1,3-bis(2,4-dihydroxyphenyl)propane

Dioscorea spp.

−101.7

−101.1

1,3-bis(2-hydroxy-4-methoxyphenyl)propane

Dioscorea spp.

−97.1

−94.9

burkinabin A

Echinacea spp.

−97.6

−100.6

burkinabin B

Echinacea spp.

−101.2

−85.1

caffeic acid

Echinacea spp.

−72.1

−74.5

caffeoyl-p-coumaroyltartaric acid

Echinacea spp.

−98.3

−129.8

caffeoylferuloyltartaric acid

Echinacea spp.

−76.1

−96.2

trans-caffeoylglycolic acid

Cimicifuga racemosa

−87.3

−96.7

caftaric acid

Echinacea spp.

−105.7

−112.1

chicoric acid

Echinacea spp.

−99.1

−116.1

cimicifugic acid A

Cimicifuga racemosa

−102.9

−124.1

cimicifugic acid B

Cimicifuga racemosa

−114.4

−120.5

cimicifugic acid F

Cimicifuga racemosa

−126.2

−125.2

cimicifugic acid G

Cimicifuga racemosa

−101.4

−113.4

cimiciphenol

Cimicifuga racemosa

−113.2

−119.4

cimiciphenone

Cimicifuga racemosa

−109.0

−120.8

cimifugin

Cimicifuga racemosa

−93.6

−97.1

cimiracemate A

Cimicifuga racemosa

−113.9

−120.9

cimiracemate B

Cimicifuga racemosa

−114.4

−127.3

cimiracemate C

Cimicifuga racemosa

−110.5

−115.8

cimiracemate D

Cimicifuga racemosa

−104.2

−128.5

p-coumaric acid

Trigonella foenum-graecum

−65.8

−69.0

diferuloyltartaric acid

Echinacea spp.

−102.6

−88.7

6,7-dihydroxy-1,1-dimethylisochroman

Dioscorea spp.

−68.4

−67.5

2-(3,7-dimethyl-2,6-octadienyl)-4-hydroxy-6-methoxyacetophenone

Dioscorea spp.

−99.6

−104.8

ferulic acid

Echinacea spp.

−70.7

−78.2

fukiic acid

Cimicifuga racemosa

−83.4

−88.1

fukinolic acid

Cimicifuga racemosa

−113.6

−127.3

irbic acid

Centella asiatica

no dock

−17.6

isoferulic acid

Cimicifuga racemosa

−68.6

−73.7

licoagroaurone

Glycyrrhiza glabra

−109.5

−117.9

licoagrone

Glycyrrhiza glabra

no dock

no dock

paeonol

Dioscorea spp.

−59.4

−62.5

(S)-phaselic acid

Trifolium pratense

−99.7

−109.6

trichocarpinine

Echinacea spp.

−84.4

−92.4

Table 11

MolDock molecular docking energies (kJ/mol) for sesquiterpenoids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

bilobanol

Ginkgo biloba

−84.8

−89.2

bisabolangelone

Angelica sinensis

−80.2

−90.4

cinnamoyldihydroxynardol

Echinacea spp.

−99.5

−98.5

cinnamoylechinadiol

Echinacea spp.

−83.6

−120.8

cinnamoylechinaxanthol

Echinacea spp.

−87.6

−94.9

cinnamoylepoxyechinadiol

Echinacea spp.

−86.4

−107.9

Table 12

MolDock molecular docking energies (kJ/mol) for steroids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

campesterol

Centella asiatica

−71.1

−108.8

Ptychopetalum olacoides

P. uncinatum

Sambucus nigra

Tribulus terrestris

Trifolium pratense

chiapagenin

Dioscorea spp.

−61.5

no dock

chlorogenin

Tribulus terrestris

−5.7

no dock

cholest-5-ene-3,12,16,22-tetrol

Dioscorea spp.

−49.5

−82.0

correllogenin

Dioscorea spp.

−64.3

no dock

cryptogenin

Dioscorea spp.

−51.3

−74.8

2,3-dihydroxypregn-16-en-20-one

Tribulus terrestris

−105.3

−116.6

2,3-dihydroxyspirost-4-en-12-one

Tribulus terrestris

no dock

no dock

3,16-dihydroxypregn-5-en-20-one

Dioscorea spp.

−91.9

−116.6

3,16-dihydroxypregnane-12,20-dione

Tribulus terrestris

−93.7

−95.6

3,21-dihydroxypregna-5,16-dien-20-one

Dioscorea spp.

−103.1

−121.4

diosbulbisin A

Dioscorea spp.

no dock

no dock

diosbulbisin B

Dioscorea spp.

no dock

no dock

diosbulbisin C

Dioscorea spp.

no dock

no dock

diosbulbisin D

Dioscorea spp.

−59.9

no dock

diosgenin

Dioscorea spp.

−58.9

no dock

Tribulus terrestris

Trigonella foenum-graecum

diosgenin acetate

Dioscorea spp.

no dock

no dock

diotigenin

Dioscorea spp.

no dock

no dock

doristerol

Dioscorea spp.

−62.1

−80.3

episarsasapogenin

Dioscorea spp.

no dock

no dock

epismilagenin

Dioscorea spp.

−53.4

no dock

ergost-5-ene-3,26-diol

Dioscorea spp.

−71.3

−108.6

ergost-8(14)-en-3-ol

Dioscorea spp.

−69.5

−98.5

furost-20(22)-ene-2,3,26-triol

Tribulus terrestris

−37.8

−44.1

furost-20(22)-ene-3,26-diol

Tribulus terrestris

−10.1

−45.5

furost-5-ene-3,16,26-triol

Tribulus terrestris

−49.7

−45.8

furost-5-ene-3,22,26,27-tetrol

Dioscorea spp.

−35.1

−4.6

furost-5-ene-3,22,26-triol

Dioscorea spp.

−48.2

−24.1

Tribulus terrestris

furosta-5,20(22)-diene-3,26-diol

Dioscorea spp.

−30.4

−36.0

furostane-1,2,3,22,26-pentol

Dioscorea spp.

−40.7

−51.4

gentrogenin

Dioscorea spp.

−49.8

no dock

gitogenin

Tribulus terrestris

no dock

no dock

Trigonella foenum-graecum

globosterol

Ginkgo biloba

−31.4

−11.3

hecogenin

Tribulus terrestris

no dock

no dock

26-hydroxyfurosta-4,20(22)-diene-3,12-dione

Tribulus terrestris

−20.2

−32.5

24-hydroxyspirost-4-ene-3,12-dione

Tribulus terrestris

no dock

no dock

19-hydroxyyonogenin

Dioscorea spp.

no dock

no dock

igagenin

Dioscorea spp.

−41.8

no dock

isochiapagenin

Dioscorea spp.

−49.1

no dock

isodiotigenin

Dioscorea spp.

−54.5

no dock

isonarthogenin

Dioscorea spp.

−61.3

no dock

kogagenin

Dioscorea spp.

−56.5

no dock

marianine

Silybum marianum

−5.9

−57.3

24-methylenelanost-8-ene-3,25,28-triol

Silybum marianum

−29.3

−38.3

neogitogenin

Tribulus terrestris

−55.1

no dock

neohecogenin

Tribulus terrestris

−39.7

no dock

neokammogenin

Dioscorea spp.

no dock

no dock

neotigogenin

Tribulus terrestris

−51.9

no dock

Trigonella foenum-graecum

neoyonogenin

Dioscorea spp.

no dock

no dock

pentandroside F (aglycone)

Tribulus terrestris

−37.5

−41.4

Trigonella foenum-graecum

prazerigenin A

Dioscorea spp.

−56.1

no dock

prazerigenin B

Dioscorea spp.

−53.2

no dock

prazerigenin C

Dioscorea spp.

−60.7

no dock

pregnadienolone

Dioscorea spp.

−102.7

−115.4

protoyonogenin (aglycone)

Dioscorea spp.

−28.9

−17.8

ruscogenin

Tribulus terrestris

−6.9

no dock

sarsasapogenone

Dioscorea spp.

−51.4

no dock

β-sitosterol

Tribulus terrestris

−65.0

−102.8

smilagenone

Dioscorea spp.

no dock

no dock

25R-spirosta-3,5-diene

Trigonella foenum-graecum

−54.8

no dock

spirost-4-ene-3,12-dione

Tribulus terrestris

−67.9

no dock

spirost-4-ene-3,6,12-trione

Tribulus terrestris

no dock

no dock

spirosta-3,5-dien-12-one

Tribulus terrestris

−50.5

no dock

spirostane-3,23,24-triol

Tribulus terrestris

no dock

no dock

spirostane-3,6,12-trione

Tribulus terrestris

no dock

no dock

steroid G4

Dioscorea spp.

no dock

no dock

stigmast-8(14)-en-3-ol

Dioscorea spp.

−45.3

−75.3

terrestrosin K (aglycone)

Tribulus terrestris

no dock

−60.5

1,2,3,16-tetrahydroxypregnan-20-one

Dioscorea spp.

−88.7

−48.9

tigogenin

Tribulus terrestris

no dock

no dock

Trigonella foenum-graecum

tokorogenin

Dioscorea spp.

−50.3

no dock

tribufuroside C (aglycone)

Tribulus terrestris

no dock

−65.4

tribufuroside D (aglycone)

Tribulus terrestris

no dock

−13.1

tribufuroside I (aglycone)

Tribulus terrestris

−2.9

−35.0

tribufuroside J (aglycone)

Tribulus terrestris

no dock

−34.3

trigoneoside (aglycone)

Trigonella foenum-graecum

−53.8

−55.6

2,3,4-trihydroxypregn-16-en-20-one

Dioscorea spp.

−82.7

−71.9

yamogenin

Dioscorea spp.

−59.4

no dock

Trigonella foenum-graecum

yonogenin

Dioscorea spp.

no dock

no dock

Table 13

MolDock molecular docking energies (kJ/mol) for stilbenoids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

3-acetoxy-4′,5-dihydroxy-3′-prenyldihydrostilbene

Glycyrrhiza glabra

−119.0

−118.7

batatasin II

Dioscorea spp.

−84.6

−94.7

batatasin III

Dioscorea spp.

−83.3

−92.6

batatasin IV

Dioscorea spp.

−80.7

−93.4

batatasin V

Dioscorea spp.

−88.6

−98.4

demethylbatatasin IV

Dioscorea spp.

−81.1

−92.3

dihydropinosylvin

Dioscorea spp.

−77.9

−86.2

dihydropinosylvin methyl ether

Dioscorea spp.

−74.1

−89.3

dihydroresveratrol

Dioscorea spp.

−83.0

−94.4

2,4′-dihydroxy-3′,5′-dimethoxybibenzyl

Dioscorea spp.

−87.4

−100.3

gancaonin R

Glycyrrhiza uralensis

−102.1

−107.0

licoagrodione

Glycyrrhiza glabra

−98.2

−116.9

piceatannol

Picea abies

−85.9

−100.3

3,3′,4,5′-tetrahydroxy-4′,5-diprenylbibenzyl

Glycyrrhiza glabra

−108.9

−117.1

2,2′,5,5′-tetrahydroxy-3-methoxybibenzyl

Dioscorea spp.

−87.4

−99.0

3,3′,4,5′-tetrahydroxy-5-prenylbibenzyl

Glycyrrhiza glabra

−111.4

−115.0

3,3′,5′-trihydroxy-4-methoxybibenzyl

Glycyrrhiza glabra

−88.0

−97.7

3,4′,5-trihydroxy-3′,4-diprenylbibenzyl

Glycyrrhiza glabra

−107.4

−111.0

3,3′,5′-trihydroxy-4-methoxy-5-prenylbibenzyl

Glycyrrhiza glabra

−111.4

−113.6

3,4′,5-trihydroxy-3′-prenyldihydrostilbene

Glycyrrhiza glabra

−106.3

−112.0

tristin

Dioscorea spp.

−91.1

−98.7

uralstilbene

Glycyrrhiza glabra

−101.7

−122.1

Table 14

MolDock molecular docking energies (kJ/mol) for triterpenoids with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

actaeaepoxide

Cimicifuga racemosa

no dock

no dock

acteol

Cimicifuga racemosa

−18.4

no dock

acteol-12-acetate

Cimicifuga racemosa

no dock

no dock

acteol-26-ketone

Cimicifuga racemosa

−42.3

no dock

12β-acetoxycimigenol

Cimicifuga racemosa

no dock

no dock

25-acetoxy-12β-hydroxycimigenol

Cimicifuga racemosa

no dock

no dock

24-acetoxyisodahurinol

Cimicifuga racemosa

no dock

no dock

23-acetoxyshengmanol

Cimicifuga racemosa

no dock

no dock

3′-acetylcimicifugoside (aglycone)

Cimicifuga racemosa

−30.4

−25.5

α-amyrin

Sambucus nigra

no dock

−5.6

β-amyrin

Glycyrrhiza glabra

no dock

no dock

α-amyrone

Sambucus nigra

no dock

no dock

25-anhydrocimigenol-12β-acetoxy

Cimicifuga racemosa

no dock

no dock

asiatic acid

Centella asiatica

no dock

no dock

asiaticoside G (aglycone)

Centella asiatica

no dock

no dock

betulafolienetriol

Centella asiatica

−73.1

−67.8

betulin

Sambucus nigra

no dock

−26.3

betulinic acid

Glycyrrhiza glabra

no dock

−43.9

caulophyllogenin

Cimicifuga racemosa

no dock

no dock

centellasapogenol A

Centella asiatica

no dock

no dock

centelloside A (aglycone)

Centella asiatica

−59.8

−75.5

cimicidol-3-one

Cimicifuga racemosa

−47.0

−65.6

cimigenol

Cimicifuga racemosa

no dock

no dock

cimipodocarpaside (aglycone)

Cimicifuga racemosa

−28.8

−4.4

cimiracemoside F (aglycone)

Cimicifuga racemosa

no dock

no dock

cimiracemoside H (aglycone)

Cimicifuga racemosa

no dock

no dock

cimiracemoside I (aglycone)

Cimicifuga racemosa

−66.2

no dock

corosolic acid

Centella asiatica

no dock

no dock

9(11)-dehydroglycyrrhetic acid

Glycyrrhiza glabra

no dock

no dock

26-deoxyacteol

Cimicifuga racemosa

−39.7

no dock

11-deoxoglycyrrhetic acid

Glycyrrhiza glabra

no dock

no dock

desoxoglabrolide

Glycyrrhiza glabra

no dock

no dock

12β,21-dihydroxycimigenol

Cimicifuga racemosa

no dock

no dock

2,3-dihydroxy-5-(hydroxymethyl)-24-norolean-12-en-28-oic acid

Centella asiatica

no dock

no dock

3,24-dihydroxy-11,13(18)-oleanadien-30-oic acid methyl ester

Glycyrrhiza glabra

no dock

no dock

3,24-dihydroxy-9(11),12-oleanadien-30-oic acid

Glycyrrhiza glabra

no dock

no dock

23-epi-26-deoxyacteol

Cimicifuga racemosa

−53.0

no dock

glabric acid

Glycyrrhiza glabra

no dock

no dock

glabrolide

Glycyrrhiza glabra

no dock

no dock

glycyrrhetic acid

Glycyrrhiza glabra

no dock

no dock

18α-glycyrrhetic acid

Glycyrrhiza glabra

no dock

no dock

glycyrrhetol

Glycyrrhiza glabra

no dock

no dock

21-hydroxycimigenol

Cimicifuga racemosa

no dock

no dock

18α-hydroxyglycyrrhetic acid

Glycyrrhiza glabra

no dock

no dock

24-hydroxyglycyrrhetic acid

Glycyrrhiza glabra

no dock

no dock

28-hydroxyglycyrrhetic acid

Glycyrrhiza glabra

no dock

no dock

21-hydroxyisoglabrolide

Glycyrrhiza glabra

no dock

no dock

24-hydroxyliquiritic acid

Glycyrrhiza glabra

no dock

no dock

6β-hydroxymaslinic acid

Centella asiatica

no dock

no dock

isoglabrolide

Glycyrrhiza glabra

no dock

no dock

isothankunic acid

Centella asiatica

no dock

no dock

lanosta-5,24-dien-3-ol

Glycyrrhiza glabra

−55.6

−52.3

liquiridiolic acid

Glycyrrhiza glabra

no dock

no dock

liquiritic acid

Glycyrrhiza glabra

no dock

no dock

liquoric acid

Glycyrrhiza glabra

no dock

no dock

lupeol

Ptychopetalum olacoides

no dock

−40.5

P. uncinatum

Sambucus nigra

madasiatic acid

Centella asiatica

no dock

no dock

madecassic acid

Centella asiatica

no dock

no dock

neocimicigenol

Cimicifuga racemosa

no dock

no dock

oleanolic acid

Sambucus nigra

no dock

no dock

quasipanaxadiol

Centella asiatica

no dock

−35.5

shengmanol

Cimicifuga racemosa

no dock

−3.0

silymin A

Sambucus nigra

no dock

no dock

silymin B

Sambucus nigra

no dock

no dock

terminolic acid

Centella asiatica

no dock

no dock

2,3,20,23-tetrahydroxy-28-ursanoic acid

Centella asiatica

no dock

no dock

2,3,23-trihydroxy-20-ursen-28-oic acid

Centella asiatica

no dock

no dock

3,6,23-trihydroxy-12-ursen-28-oic acid

Centella asiatica

no dock

no dock

uncargenin C

Centella asiatica

no dock

no dock

ursolic acid

Sambucus nigra

no dock

no dock

zemoside A (aglycone)

Centella asiatica

no dock

no dock

Table 15

MolDock molecular docking energies (kJ/mol) for miscellaneous phytochemicals with human estrogen receptors α and β

Compound

Plant Source

ERα

ERβ

10-angeloylbutylphthalide

Angelica sinensis

−96.9

−107.1

ansaspirolide

Angelica sinensis

−98.5

−91.5

asiaticin

Centella asiatica

−96.7

−109.0

3a,7′a:7a,3′a-diligustilide

Angelica sinensis

−94.5

−69.6

3a,8′:6,3′-diligustilide

Angelica sinensis

−91.3

−72.6

3a,8′:6,3′-diligustilidetriepimer

Angelica sinensis

−98.0

−78.1

dioscorealide A

Dioscorea spp.

−92.1

−97.1

dioscorealide B

Dioscorea spp.

−86.2

−98.7

diospongin A

Dioscorea spp.

−95.1

−104.8

diospongin B

Dioscorea spp.

−97.1

−103.9

diospongin C

Dioscorea spp.

−96.1

−107.9

gelispirolide

Angelica sinensis

−64.7

−84.8

homosenkyunolide H

Angelica sinensis

−83.8

−88.7

homosenkyunolide I

Angelica sinensis

−84.3

−92.2

homosilphiperfoloic acid

Centella asiatica

−83.0

−77.3

levistolide A

Angelica sinensis

−86.5

−86.4

neodiligustilide

Angelica sinensis

−78.3

−6.6

orobanchyl acetate

Trifolium pratense

−111.3

−122.8

riligustilide

Angelica sinensis

−71.2

−81.6

senkyunolide O

Angelica sinensis

−84.8

−91.3

sinaspirolide

Angelica sinensis

−86.8

−66.2

3,3a,7a,8-tetrahydro-3,6′:7a,7′-diligustilid-8-one

Angelica sinensis

−80.8

−99.2

estradiol

Positive control

−92.0

−100.0

zearalenone

Positive control

−104.1

−104.9

Results

Alkaloids

The alkaloid ligands examined in this study are shown in Figure 2. The molecular docking results for the alkaloids are summarized in Table 2. Of the alkaloids examined in this study, cis- and trans-clovamide, with docking energies of −119.8 and −113.6 kJ/mol, respectively, and N-trans-feruloyltyramine (E dock = −103.1 kJ/mol) were found to dock well with ERα. Their docking energies were more exothermic than those of estradiol, −92.0 kJ/mol and the corresponding co-crystallized ligand genistein, −93.4 kJ/mol, and the clovamides were more exothermic than zearalenone (E dock = −104.1 kJ/mol). The co-crystallized ligand, genistein, and the clovamide and feruloylyramine ligands have similar positions in the binding site (Figure 44). Phe 404, Leu 525, Leu 346, Leu 387, and Leu 391 form a hydrophobic pocket around the docked alkaloids. Phe 404 exhibited edge-to-face π–π interactions between the phenyl substituent of Phe with the caffeic or ferulic substituents of the alkaloids and with the hydroxyphenyl substituent of genistein. Notable hydrogen bonds in the lowest-energy docked pose of cis-clovamide were the 3-OH and 4-OH of the cis-caffeic moiety with the carboxylate residue of Glu 353 and the 3-OH group with the guanidine residue of Arg 394 (Figure 45). The docked trans-clovamide had hydrogen bonds between the 4-OH of the caffeate with the guanidine of Arg 394 and the carbonyl group of Leu 387 and the 3-OH group with the carboxylate of Glu 353. Hydrogen bonds were formed between the 4-OH group on the ferulyl substituent of N-trans-feruloyltyramine and carbonyl group of Leu 387, the guanidine group of Arg 394, and the carboxylate of Glu 353.
https://static-content.springer.com/image/art%3A10.1186%2Fs40203-015-0008-z/MediaObjects/40203_2015_8_Fig44_HTML.gif
Figure 44

Lowest-energy docked poses of alkaloids [ N-trans -feruloyltyramine (aqua), cis- clovamide (red), and trans- clovamide (blue) along with the co-crystallized ligand, genistein (green)] with ERα (PDB 1X7R). A: Docked poses showing the entire ribbon structure of the protein. B: Close-up of the docked poses.

https://static-content.springer.com/image/art%3A10.1186%2Fs40203-015-0008-z/MediaObjects/40203_2015_8_Fig45_HTML.gif
Figure 45

Lowest-energy docked pose of cis- clovamide with ERα (PDB 1X7R) showing the principle amino acid contacts in the binding site. Hydrogen bonds are indicated by blue dashed lines.

Similarly, cis-clovamide, trans-clovamide, and N-trans-feruloyltyramine were the alkaloids that docked well with ERβ. Their docking energies (−124.9, −122.0, and −113.8 kJ/mol, respectively) were more exothermic than those of estradiol, −100.0 kJ/mol, zearalenone, −104.9 kJ/mol, and the corresponding co-crystallized ligand 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol, −107.9 kJ/mol. The alkaloid and the co-crystallized ligand occupied similar positions in the binding site, a hydrophobic pocket formed by Leu 298, Phe 356, Leu 339, and His 475. Phe 356 exhibited edge-to-face π–π interactions with the caffeic or ferulic substituents of the docked alkaloid ligands as well as with the hydroxyphenyl substituent of the co-crystallized ligand. There were two notable hydrogen bonds formed between the 4-OH group on the ferulyl substituent of N-trans-feruloyltyramine and the guanidine group of Arg 346, and the carboxylate of Glu 305 (Figure 46). These same two residues formed hydrogen bonds with the 4-hydroxyphenyl group of the co-crystallized ligand. The caffeoyl group of cis-clovamide formed hydrogen bonds with Glu 305 and Leu 298. trans-Clovamide, however, formed hydrogen bonds with Leu 339, Arg 346, and Glu 305.
https://static-content.springer.com/image/art%3A10.1186%2Fs40203-015-0008-z/MediaObjects/40203_2015_8_Fig46_HTML.gif
Figure 46

Lowest-energy docked pose of N-trans- feruloyltyramine with ERβ (PDB 1X7B) showing the principle amino acid contacts in the binding site. Hydrogen bonds are indicated by blue dashed lines.

Chalcones

The structures of the chalcones are shown in Figure 3, while the docking energies are summarized in Table 3. Xanthohumol was the strongest docking chalcone with ERα. Its docking energy, −116.8 kJ/mol, is more exothermic than those of estradiol, −92.0 kJ/mol, zearalenone, −104.1 kJ/mol, and the corresponding co-crystallized ligand genistein, −93.4 kJ/mol. The 4-OH group of xanthohumol forms three hydrogen-bonds with the protein (the carboxylate of Glu 353, the guanidine of Arg 394, and the carbonyl oxygen of Phe 404). The 4′-OH group of xanthohumol forms hydrogen-bonds with the imidazole N-H of His 524 and the carbonyl oxygen of Gly 521. Kanzonol Y (E dock = −111.2 kJ/mol) and licochalcone B (E dock = −107.8 kJ/mol) were the only other chalcone ligands to dock well with ERα.

Of the chalcone ligands examined, kanzonol Y (E dock = −122.4 kJ/mol), xanthohumol (E dock = −116.8 kJ/mol), and licoagrochalcone A (E dock = −115.5 kJ/mol), docked best with ERβ. Their docking energies were decidedly more exothermic than those of estradiol, zearalenone, and the corresponding co-crystallized ligand 2-(5-hydroxy-naphthalen-1-yl)-1,3-benzooxazol-6-ol (E dock = −109.2 kJ/mol). Apparently, the hydrophobic prenyl groups allow for stronger docking. Thus, kanzonol Y docked to ERβ much better than the non-prenylated α,2′,4,4′-tetrahydroxydihydrochalcone (E dock = −105.0 kJ/mol). In the lowest-energy docked pose of kanzonol Y, the 3-prenyl group is sandwiched between the hydrophobic residues of Phe 356 and Leu 339, while the 5′-prenyl group is sandwiched between Leu 476 and Thr 299 (Figure 47). It has been shown that prenylation of flavonoids and related compounds does alter the estrogenic activity and often results in antiestrogenic activity (Kretzschmar et al. 2010; Simons et al. 2012).
https://static-content.springer.com/image/art%3A10.1186%2Fs40203-015-0008-z/MediaObjects/40203_2015_8_Fig47_HTML.gif
Figure 47

Lowest-energy docked pose of the prenylated chalcone kanzonol Y with ERβ (PDB 1X7J) showing the hydrophobic amino acid contacts with the isoprenyl groups of the ligand.

Coumarins

The MolDock docking energies of the coumarins are summarized in Table 4, and the structures of the coumarins are shown in Figures 4 and 5. Glabrene and pratenol B were the strongest docking coumarins with ERα (E dock = −104.8 kJ/mol), more exothermic than either estradiol (−92.0 kJ/mol) or genistein (−93.4 kJ/mol), and comparable to zearalenone (−104.1 kJ/mol). The 7-hydroxychromene moieties of both glabrene and pratenol B are held in a hydrophobic pocket formed by Leu 387, Phe 404, Met 388, and Leu 391. Furthermore, there are edge-to-face π–π interactions between Phe 404 and the chromene benzene rings of the ligands, as well as hydrogen bonds between the 7-OH group of the chromene and the guanidine group of Arg 394 and the carboxylate of Glu 356, analogous to the co-crystallized ligand genistein. Additionally, one of the carboxylates of pratenol B forms a hydrogen bond with imidazole substituent NH group of His 475.

In addition to glabrene (E dock = −114.9 kJ/mol) and pratenol B (E dock = −112.0 kJ/mol), mirificoumestan docked strongly with ERβ with a docking energy of −113.0 kJ/mol. These compounds docked more exothermically than estradiol, zearalenone, or the co-crystallized ligand [5-hydroxy-2-(4-hydroxyphenyl)-1-benzofuran-7-yl]acetonitrile (E dock = −107.7 kJ/mol). Glabrene docked into the hydrophobic pocket formed by Leu 298, Leu 339, and Phe 356. Phe 356 exhibited edge-to-face π–π interactions with the hydroxychromene substituent of glabrene. There was a hydrogen bond between the imidazole substituent NH group of His 475 and the 5′-OH group of glabrene, and three hydrogen bonding interactions were seen between the 7-OH group of glabrene and the carbonyl group of Leu 339, the guanidine moiety of Arg 346, and the carboxylate of Glu 305.

Diterpenoids

The structures for the diterpenoid ligands examined in this work are shown in Figures 6, 7, 8, and 9, and the docking energies are listed in Table 5. The strongest docking diterpenoids with ERα were diosbulbin F, diosbulbin K, and diosbulbin L (E dock = −111.2, −112.1, and −110.8 kJ/mol, respectively). Each of these ligands docked in the hydrophobic binding pocket with the furan group forming a hydrogen bond to the guanidine of Arg 394. The methyl ester of diosbulbin F and the carboxylate of diosbulbin L also formed hydrogen bonds to the imizadole of His 524. These three diterpenoids also docked strongly to ERβ. In addition, diosbulbin F, diosbulbin H, ptycho-6α,7α-diol, and ptycholide IV all had docking energies more exothermic (E dock = −114.8, −114.1, −122.9, and −114.7 kJ/mol) than the co-crystallized ligand, 2-(5-hydroxynaphthalen-1-yl)-1,3-benzooxazol-6-ol (E dock = −111.3 kJ/mol). Ptycho-6α,7α-diol docked with ERβ with hydrogen bonds between the lactone carbonyl of the ligand and Arg 346 and the 6-OH group of the ligand with His 475.

Flavonoids

The structures of the flavonoid ligands examined in this work are shown in Figures 10, 11, 12, 13, 14, 15, 16, and 17, and the docking energies are listed in Table 6. Of the flavonoids, luteolin-8-propenoic acid docked the strongest to ERα, with a docking energy of −113.127 kJ/mol, more exothermic than those of estradiol, zearalenone, or genistein. A common docking orientation for phenolic ligands in ERα is the hydrophobic pocket of Leu 387, Phe 404, Met 388, and Leu 391, along with edge-to-face π–π interactions with Phe 404, and hydrogen bonds between the phenolic –OH group and the guanidine group of Arg 394 and the carboxylate of Glu 356. The 7-OH group of the ligand made an additional hydrogen bond with the carbonyl oxygen of Gly 521. No other flavonoid ligands showed notably strong docking with ERα.

Luteolin-8-propenoic acid was also the strongest docking flavonoid with ERβ (E dock = −123.1 kJ/mol), is far more exothermic than estradiol, zearalenone, and the co-crystallized ligand, 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol (E dock = −106.2 kJ/mol). As observed in other phenolic ligands with ERβ, luteolin-8-propenoic acid occupied the hydrophobic pocket formed by Leu 298, Leu 339, and Phe 356; edge-to-face π–π interactions of the phenolic ligand with Phe 356 and hydrogen boding of the phenolic –OH group with the carbonyl group of Leu 339, the guanidine group of Arg 346, and the carboxylate of Glu 305. The 7-OH group of the ligand made additional hydrogen bonds with the carbonyl oxygen of Gly 472 and His 475. Casticin (E dock = −106.4 kJ/mol), gonzalitosin (E dock = −106.3 kJ/mol), gossypetin (E dock = −105.7 kJ/mol), laricitrin (E dock = −107.3 kJ/mol), myricetin (E dock = −106.2 kJ/mol), quercetin (E dock = −106.0 kJ/mol), santin (E dock = −108.0 kJ/mol), and tricetin (E dock = −106.2 kJ/mol), all had more exothermic docking energies than estradiol or zearalenone but were less exothermic than the co-crystallized ligand, 2-(5-hydroxynaphthalen-1-yl)-1,3-benzooxazol-6-ol (E dock = −111.3 kJ/mol).

Isoflavonoids

The docking energies of the isoflavonoids are summarized in Table 7 and the structures are shown in Figure 18, 19, and 20. Genistein is the quintessential estrogenic isoflavonoid, but it is a weaker docking ligand than estradiol or zearalenone for either ERα or ERβ. The strongest docking isoflavonoid with ERα was the aglycone of licoagroside A (E dock = −100.5 kJ/mol), but this was weaker than zearalenone. On the other hand, several isoflavonoid ligands docked to ERβ more strongly than zearalenone: licoagroside A aglycone (E dock = −107.7 kJ/mol), 1-methoxyphaseollin (E dock = −110.5 kJ/mol), pratensein (E dock = −106.4 kJ/mol), and 3′,5,7-trihydroxy-5′-methoxyisoflavone (E dock = −107.9 kJ/mol), but none of these docked more strongly than the synthetic co-crystallized ligand, 2-(5-hydroxynaphthalen-1-yl)-1,3-benzooxazol-6-ol (E dock = −111.3 kJ/mol).

Lignans

The structures and the docking energies of the lignans are shown in Figure 21 and Table 8, respectively. Nortrachelogenin and 7′-hydroxymatairesinol were the strongest docking lignans to ERα (E dock = −112.0 and −112.3 kJ/mol, respectively). Nortrachelogenin was also the strongest docking lignan to ERβ (E dock = −125.4 kJ/mol). Sesamin showed notable selectivity for ERβ over ERα (E dock = −121.8 and −99.1 kJ/mol, respectively). Nortrachelogenin occupied the same orientation and hydrogen-bonding pattern in both ERα and ERβ, with one of the phenolic –OH groups hydrogen bonded to argenine in the binding pocket (Arg 394 in ERα; Arg 346 in ERβ) and the other phenolic –OH group hydrogen bonded to the histidine (His 524 in ERα; His 475 in ERβ).

Phenanthrenoids

The docking energies and structures of phenanthrenoids are shown in Table 9 and Figure 22, respectively. None of the phenanthrenoids examined in this work showed docking energies lower than estradiol or zearalenone for ERα or ERβ.

Miscellaneous phenolics

The docking energies for miscellaneous herbal phenolic compounds are listed in Table 10, and the structures are shown in Figures 23, 24, and 25. The strongest docking ligands of the miscellaneous phenolic compounds for ERα was cimicifugic acid F (E dock = −126.2 kJ/mol), and this ligand also docked strongly with ERβ (E dock = −125.2 kJ/mol). Several other phenolic ligands docked with very exothermic energies to ERβ: the aglycone of agnucastoside C (E dock = −130.0 kJ/mol), caffeoyl-p-coumaroyl tartaric acid (E dock = −129.8 kJ/mol), cimiracemate B (E dock = −127.3 kJ/mol), cimiracemate D (E dock = −128.5 kJ/mol), and fukinolic acid (E dock = −127.3 kJ/mol).

Analogous to other phenolic compounds (see above), the cinnamate moiety of the lowest-energy pose of cimicifugic acid F in ERα shows edge-to-face π–π interactions with Phe 404, and hydrogen bonding between the –OCH3 group and the guanidine group of Arg 394. Additionally, the 3-carboxylate group of the ligand is hydrogen-bonded to His 524, and the phenolic group fits into a hydrophobic pocket formed by Met 388, Met 421, and Ile 424.

The lowest-energy docked pose of the aglycone of agnucastoside C with ERβ, as with other phenolic compounds (see above), has the p-coumarate phenolic –OH group hydrogen bonded to the carbonyl group of Leu 339 and the guanidine group of Arg 346, and edge-to-face π–π interactions of the phenolic ligand with Phe 356. The cyclic hemiacetal group is hydrogen bonded to His 475.

Sesquiterpenoids

Of the sesquiterpenoids, only cinnamoylechinadiol gave a notable docking energy (−120.8 kJ/mol) with ERβ (Figure 26, Table 11).

Steroids

The steroidal ligands examined in this study are shown in Figures 27, 28, 29, 30, 31, 32, 33, and 34, and their docking energies are listed in Table 12. Several pregnane steroids exhibited docking energies less than the co-crystallized ligand 2-(5-hydroxynaphthalen-1-yl)-1,3-benzooxazol-6-ol (E dock = −111.3 kJ/mol) for ERβ: 2,3-Dihydroxypregn-16-en-20-one (E dock = −116.6 kJ/mol), 3,16-dihydroxypregn-5-en-20-one (E dock = −116.6 kJ/mol), 3,21-dihydroxypregna-5,16-dien-20-one (E dock = −121.4 kJ/mol), and pregnadienolone (E dock = −115.4 kJ/mol). The lowest-energy docked poses of the pregnane ligands show them all to adopt the same orientation (Figure 48) with key hydrogen-bonding interactions of the 3-OH group of the steroids with the guanidine of Arg 346 and the amide carbonyl of Leu 339, and the 20-ketone group of the ligand with the imidazole N-H of His 475. Two ligands, 3,16-dihydroxypregn-5-en-20-one and 3,21-dihydroxypregna-5,16-dien-20-one, showed selectivity for ERβ over ERα (24.8 and 18.4 kJ/mol, respectively).
https://static-content.springer.com/image/art%3A10.1186%2Fs40203-015-0008-z/MediaObjects/40203_2015_8_Fig48_HTML.gif
Figure 48

Lowest-energy docked poses of pregnane steroids [2,3-dihydroxypregn-16-en-20-one (magenta), 3,16-dihydroxypregn-5-en-20-one (dark green), 3,21-dihydroxypregna-5,16-dien-20-one (white), and pregnadienolone (bright green)] with ERβ (PDB 1U3R). A: Docked poses showing the entire ribbon structure of the protein. B: Close-up of the docked poses.

Stilbenoids

Structures and docking energies for the stilbenoid ligands are shown in Figures 35 and 36, and Table 13, respectively. Several stilbenoid ligands showed notably strong docking energies; lower than estradiol, zearalenone, or the respective co-crystallized ligands: 3-acetoxy-4′,5-dihydroxy-3′-prenyldihydrostilbene (E dock to ERα = −119.0 kJ/mol), licoagrodione (E dock to ERβ = −116.9 kJ/mol), 3,3′,4,5′-tetrahydroxy-4′,5-diprenylbibenzyl (E dock to ERβ = −117.1 kJ/mol), 3,3′,4,5′-tetrahydroxy-5-prenylbibenzyl (E dock to ERβ = −115.0 kJ/mol), and uralstilbene (E dock to ERβ = −122.1 kJ/mol). Prenylation of stilbenoids seems to improve docking energies by about 20 kJ/mol.

Triterpenoids

Docking energies are presented in Table 14 and structures of triterpenoid ligands are illustrated in Figures 37, 38, 39, 40, and 41. Unlike the pregnane steroids, there were no triterpenoid ligands that showed good docking with either ERα or ERβ.

Miscellaneous phytochemicals

Several miscellaneous phytochemicals found in herbal supplements were included in this study (Table 15, Figures 42 and 43). Of these ligands, orobanchyl acetate gave excellent docking energies for both ERα and ERβ (E dock = −111.3 and −122.8 kJ/mol, respectively).

Discussion

Angelica sinensis

Dong quai (Angelica sinensis root) has been used in Chinese traditional medicine for thousands of years for various female health conditions (e.g., dysmenorrhea, pelvic pain, symptoms of menopause) (Chye 2006; Al-Bareeq et al. 2010; Fang et al. 2012). In spite of its history, dong quai provided no clinical relief of menopausal symptoms (Hirata et al. 1997). In fact, dong quai has been shown to stimulate the growth of MCF-7 (ER+ human mammary carcinoma) cells (Lau et al. 2005), but does not bind either ERα or ERβ (Liu et al. 2001). The plant contains several miscellaneous phytochemicals, only two of which have notable docking energies, 10-angeloylbutylphthalide (−107.1 kJ/mol with ERβ) and angeliferulate (−110.7 and −121.5 kJ/mol with ERα and ERβ, respectively).

Centella asiatica

Centella asiatica (gotu kola) has been used in Ayurvedic traditional medicine for cognitive enhancement (Rao et al. 2005), to alleviate symptoms of anxiety and promote relaxation (Wijeweera et al. 2006), as well as for headache, body ache, asthma, ulcers, and wound healing (Kumar and Gupta 2002). Animal studies have revealed cognitive enhancement (Kumar and Gupta 2002; Rao et al. 2005), neuroprotective (Subathra et al. 2005), and anxiolytic (Wijeweera et al. 2006) effects. To our knowledge, there have been no reports on the estrogenic activity of C. asiatica.

The plant contains the flavonoids castillicetin, castilliferol, kaempferol, and quercetin; the triterpenoids 2,3,20,23-tetrahydroxy-28-ursanoic acid, 2,3,23-trihydroxy-20-ursen-28-oic acid, 2,3-dihydroxy-5-(hydroxymethyl)-24-norolean-12-en-28-oic acid, 3,6,23-trihydroxy-12-ursen-28-oic acid, 6β-hydroxymaslinic acid, asiatic acid, asiaticoside G, betulafolienetriol, centellasapogenol A, centelloside A, corosolic acid, isothankunic acid, madasiatic acid, madecassic acid, quasipanaxadiol, terminolic acid, uncargenin C and zemoside A; the steroid campesterol, and the miscellaneous compounds asiaticin, homosilphiperfoloic acid, and irbic acid. Both quercetin and asiaticin had notable exothermic docking energies with ERβ (−106.0 and −109.0 kJ/mol, respectively). Quercetin has shown preferential binding to ERβ (Kuiper et al. 1998).

Cimicifuga racemosa (syn. Actaea racemosa)

Although black cohosh extracts have demonstrated clinical efficacy against some symptoms of menopause (Lieberman 1998; McKenna et al. 2001; Liske et al. 2002; Pockaj et al. 2004; Wuttke et al. 2006), several studies have demonstrated little or no estrogenic activity (Liu et al. 2001; Kronenberg 2003; Lupu et al. 2003; Mahady 2003). The efficacy of C. racemosa extracts on post-menopausal symptoms has been attributed to partial agonism of the serotonin receptor (Burdette et al. 2003) and the μ-opiate receptor (Rhyu et al. 2006).

C. racemosa extracts have revealed several triterpenoids (Shao et al. 2000), phenylpropanoids (Chen et al. 2002) and caffeic acid derivatives (Li et al. 2003). Very few of the C. racemosa triterpenoids showed negative docking energies and are, therefore, unlikely estrogen receptor binding agents. Several C. racemosa phenolic compounds did show remarkable docking affinities for both ERα and ERβ: cimicifugic acid A, cimicifugic acid B, cimicifugic acid G, cimiciphenol, cimiciphenone, cimiracemate A, cimiracemate B, cimiracemate C, cimiracemate D, and fukinolic acid. It is likely that any estrogenic activity of C. racemosa extract (Seidlová-Wuttke et al. 2003a) is due to the presence of phenolic components rather than triterpenoids.

Dioscorea villosa

The rhizomes of wild yam, Dioscorea villosa, have been used to treat symptoms associated with menopause and premenstrual syndrome (PMS) as well as to relieve labor pains and sooth dysmenorrhea (Dutta 2015). The genus contains numerous steroidal glycosides (Sautour et al. 2006; Sautour et al. 2007; Ali et al. 2013). In this work, we have carried out in-silico screening of phytochemicals from the genus Dioscorea (Dictionary of Natural Products 2014). Of these, the diosbulbins D, F, H, J, K, and L (diterpenoids from D. bulbifera (Komori 1997; Liu et al. 2010) gave remarkable docking energies with both ERα and ERβ while the pregnane steroids 3,16-dihydroxypregn-5-en-20-one, 3,21-dihydroxypregna-5,16-dien-20-one, ergost-5-ene-3,26-diol, and pregnadienolone, showed selective docking with ERβ. Interestingly, neither furostane nor the spirostane steroids, common in Dioscorea spp. docked well with the estrogen receptors. It is worth noting that clinical studies have shown D. villosa to have little effect on menopausal symptoms (Komesaroff et al. 2001).

Echinacea spp.

Echinacea (E. angustifolia, E. pallida, and E. purpurea) is one of the most popular herbal supplements sold in the United States and has been used as a treatment for the common cold, coughs, bronchitis, upper respiratory infections, and inflammatory conditions (Percival 2000). Recent studies have demonstrated Echinacea to exhibit immune-system-stimulating activity (Block and Mead 2003). Phytochemicals that have been isolated from Echinacea spp. include chicoric acid and monomethyl and dimethyl ethers, trichocarpinine, cinnamoylechinadiol, cinnamoylechinaxanthol, cinnamoylepoxyechinadiol, cinnamoyldihydroxynardol, caftaric acid, caffeoyl-p-coumaroyltartaric acid, burkinabin A, burkinabin B, kaempferol, luteolin, and quercetin. Although Echinacea has not shown estrogenic activity (Zava et al. 1998), six phytochemicals were identified in this docking study that showed strong docking to the estrogen receptor: the flavonoid quercetin; the phenolic compounds caffeoyl-p-coumaroyltartaric acid, caftaric acid, and chicoric acid; and the sesquiterpenoids cinnamoylechinadiol and cinnamoylepoxyechinadiol.

Gingko biloba

G. biloba is commonly used as a supplement to improve cognitive abilities (Kennedy et al. 2000), and for women specifically, it has been used to treat some of the side effects accompanying menopause (Oh and Chung 2004). The extracts of G. biloba have previously been shown to exhibit feeble estrogenic effects, and act as selective estrogen receptor modulators (SERMs) with the α and β estrogen receptors (Oh and Chung 2006). Phytochemical analyses have revealed G. biloba extracts to contain the flavonoids (2R,3S,4S)-3,3′,4,4′,5,5′,7-heptahydroxyflavan, 8-(5-carboxy-2-methoxyphenyl)-5,7-dihydroxy-4′-methoxyflavone, acacetin, amentoflavone, apigenin, bilobetin, 5′-methoxybilobetin, epigallocatechin, ginkgetin, isoginkgetin, kaempferol, luteolin, quercetin, sciadopitysin, and tricetin, as well as the lignan sesamin, the sesquiterpenoids bilobanol, and the steroid globosterol. Of these, quercetin, tricetin, and sesamin gave large negative docking energies. Sesamin, in particular, docked strongly with ERβ.

Glycyrrhiza glabra

The phytochemistry of Glycyrrhiza glabra has been well studied and numerous compounds have been isolated and identified, including aurones (licoagroaurone and licoagrone), chalcones (1,2-dihydroparatocarpin A, 2,4,4′-trihydroxychalcone, 4-hydroxychalcone, cordifolin, isoliquiriteginin, licoagrochalcones A-D, licochalcones A and B, α,2′,4,4′-tetrahydroxydihydrochalcone, and kanzonol Y), coumarins (2′-O-methylglabridin, 3,4-didehydroglabridin, 3′-hydroxy-4′-methoxyglabridin, 4′-O-methylgrabridin, 4′-O-methylkanzonol W, bergapten, gancaonin F, glabrene, glabrocoumarin, glycycoumarin, glyinflanin H, hispaglabridin A, hispaglabridin B, isoglycycoumarin, isoglycyrol, kanzonol U, kanzonol V, kanzonol W, and licocoumarin A), flavonoids (3-hydroxyglabrol, 6-prenyleriodictyol, 6-prenylpinocembrin, folerogenin, glabranin, glabrol, isolicoflavonol, isoschaftoside, isoviolanthin, kaempferol, kumatakenin, licoagrodin, licoflavanone, naringenin, norwogonin, pinocembrin, quercetin, shinflavanone, and vitexin), isoflavonoids (1-methoxyphaseollin, 2′,4′,5,7-tetrahydroxy-3′,8-diprenylisoflavanone, 7-acetoxy-2-methylisoflavone, 7-hydroxy-2-methylisoflavone, 7-methoxy-2-methylisoflavone, 8-prenylphaseollinisoflavan, genistein, glabraisoflavanone A, glabraisoflavanone B, glabroisoflavanone A, glabridin, glabroisoflavanone B, glabrone, glyasperin B, glyasperin K, glyzaglabrin, glyzarin, isoderrone, isoglabrone, isomucronulatol, kanzonol R, kanzonol T, kanzonol X, licoagroside A, licoricidin, lupiwighteone, phaseollinisoflavan, prunetin, shinpterocarpin, tetrapterol G, and wighteone), the lignan licoagrocarpin, stilbenoids (3,3′,4,5′-tetrahydroxy-4′,5-diprenylbibenzyl, 3,3′,4,5′-tetrahydroxy-5-prenylbibenzyl, 3,3′,5′-trihydroxy-4-methoxy-5-prenylbibenzyl, 3,3′,5′-trihydroxy-4-methoxybibenzyl, 3,4′,5-trihydroxy-3′,4-diprenylbibenzyl, 3,4′,5-trihydroxy-3′-prenyldihydrostilbene, 3-acetoxy,4′,5-dihydroxy-3′-prenyldihydrostilbene, licoagrodione, and uralstilbene), and triterpenoids (11-deoxoglycyrrhetic acid, 18α-glycyrrhetic acid, 18α-hydroxyglycyrrhetic acid, 21-hydroxyisoglabrolide, 24-hydroxyglycyrrhetic acid, 24-hydroxyliquiritic acid, 28-hydroxyglycyrrhetic acid, 3,24-dihydroxy-11,13(18)-oleanadien-30-oic acid methyl ester, 3,24-dihydroxy-9(11),12-oleanadien-30-oic acid, 9(11)-dehydroglycyrrhetic acid, β-amyrin, betulinic acid, desoxoglabrolide, glabric acid, glabrolide, glycyrrhetic acid, glycyrrhetol, isoglabrolide, lanosta-5,24-dien-3-ol, liquiridiolic acid, liquiritic acid, and liquoric acid).

Licorice (Glycyrrhiza glabra) root has been used for thousands of years by different cultures and for a variety of reasons (Fenwick et al. 1990). Although licorice root has been suggested as a treatment for symptoms of menopause (Ojeda 2003), G. glabra root extracts have been shown to be inactive in terms of ERα or ERβ binding (Liu et al. 2001). Nevertheless, however, fractionation of G. glabra extracts has revealed several ER-modulating components (Khalaf et al. 2010; Simons et al. 2011). Glabrene binds to human ER and shows estrogenic activity (Tamir et al. 2001; Simons et al. 2011). Our in-silico docking study shows glabrene to be a strongly docking ligand to both ERα and ERβ (−104.8 and −114.9 kJ/mol, respectively). Glabridin, on the other hand, displayed ERα-selective antagonism (Simons et al. 2011), in contrast to the docking results that showed glabridin to have ERβ docking selectivity (−15.8 and −92.9 kJ/mol, respectively). The chalcones isoliquiritigenin (Tamir et al. 2001; Maggiolini et al. 2002) and licochalcone A (Rafi et al. 2000), the flavonoid quercetin (Kuiper et al. 1998), and the isoflavonoid genistein (Ososki and Kennelly 2003) also bind to human ERα and show estrogenic activity. These ligands all show negative docking energies with ERα (range from −93.2 to −99.9 kJ/mol) and ERβ (−98.9 to −107.8 kJ/mol).

Lepidium meyenii

Maca (Lepidium meyenii) is native to the central Andes of Peru (3500–4500 m asl) (Wang et al. 2007). The root has been used by native Amerindians to improve fertility, as an aphrodisiac for both men and women. Maca was found to increase sperm counts and gonadal mass in a rat model (Chung et al. 2005), to improve copulatory performance of male mice and rats (Zheng et al. 2000; Cicero et al. 2001), and to increase litter size (Ruiz-Luna et al. 2005) and pregnancy rates in female mice (Kuo et al. 2003). In adult human males, maca treatment led to increased semen volume and sperm count (Gonzales et al. 2001) and increased sexual desire (Gonzales et al. 2002; Stone et al. 2009). In addition, maca reduced sexual dysfunction in postmenopausal women (Brooks et al. 2008) and inhibited estrogen-deficient osteoporosis in ovariectomized rats (Zhang et al. 2006), but maca extracts have not shown estrogenic activity (Brooks et al. 2008). None of the L. meyenii phytochemicals investigated in this in-silico study showed remarkable docking energies, consistent with the non-estrogenic activity previously reported.

Ptychopetalum olacoides, P. uncinatum

Muira puama (bark and root extracts of P. olacoides or P. uncinatum) has been used in Amazonian Brazil during highly stressful periods, to treat CNS-related ailments, neuromuscular problems, “nervous weakness”, sexual debility, frigidity, impotence, and rheumatism (Schultes and Raffauf 1990; Siqueira et al. 1998; Duke et al. 2009). Consistent with these traditional uses, P. olacoides ethanol root extract has shown memory retrieval improvement in young and aging mice (da Silva et al. 2004), in-vitro acetylcholine esterase inhibitory activity (Siqueira et al. 2003), and prevention of stress-induced hypothalamic-pituitary-adrenal hyperactivity (Piato et al. 2008). In addition, Muira puama formulations have demonstrated efficacy in treating male erectile dysfunction and low libido (Waynberg 1994) and low sex drive in women (Waynberg and Brewer 2000). A number of clerodane diterpenoids have been isolated from P. olacoides bark (Tang et al. 2008; Tang et al. 2009; Tang et al. 2011). Several of these have given excellent docking energies with the estrogen receptor, but two in particular, ptycho-6α,7α-diol and ptycholide IV had remarkable docking to ERβ (−122.9 and −114.7 kJ/mol, respectively). To our knowledge, the estrogenic effects of Muira puama have not been investigated.

Rhodiola rosea

R. rosea is reputed to strengthen the nervous system, fight depression, enhance memory, and improve energy levels (Brown et al. 2002), which has been attributed to adaptogenic properties of the herb (Spasov et al. 2000; Darbinyan et al. 2000). The flavonoids gossypetin, herbacetin, and rhodiolin, and the lignan (+)-lariciresinol, have been identified in R. rosea. Lariciresinol showed strong docking to both ERα and ERβ. There are conflicting reports on the potential estrogenic effects of R. rosea, however (Eagon et al. 2004; Kim et al. 2005).

Sambucus nigra

The bark, leaves, flowers, fruit, and root extracts of black elderberry (Sambucus nigra) have been used traditionally to treat respiratory ailments such as bronchitis, cough, influenza, and upper respiratory infections (Zakay-Rones et al. 1995; Krawitz et al. 2011). Compounds identified in S. nigra extracts include α-amyrin, β-amyrin, α-amyrone, betulin, campesterol, cycloartenol, lupeol, oleanolic acid, quercetin, ursolic acid, and dihydrodehydrodiconiferyl alcohol (9-acetate). Of these, only the flavonoid quercetin showed good docking to the estrogen receptor. To our knowledge, there are no reports on the estrogenic activity of S. nigra extracts.

Silybum marianum

Milk thistle, Silybum marianum, extracts (silymarin) have been used for centuries to treat liver diseases (Flora et al. 1998). Silymarin contains the flavonoids apigenin, chrysoeriol, cisilandrin, eriodictyol, isocisilandrin, isosilandrin A, isosilandrin B, isosilybin A, isosilybin B, isosilybin C, isosilybin D, isosilychristin, kaempferol, naringenin, neosilyhermin A, neosilyhermin B, quercetin, silandrin A, silandrin B, silyamandin, silybin A, silybin B 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silychristin B, silydianin, silyhermin, silymonin, taxifolin; the lignan (Z)-dehydrodiconiferyl alcohol; the steroids 24-methylenelanost-8-ene-3,25,28-triol and marianine; and the triterpenoids silymin A and silymin B. Silybin B (also called silibinin) has been shown to selectively bind to the ERβ receptor rather than ERα (Seidlová-Wuttke et al. 2003b) and previous docking studies have shown selective docking to ERβ over ERα (El-Shitany et al. 2010). In contrast, our current docking study revealed that neither silybin A nor silybin B gave negative docking energies with either ERα or ERα. Quercetin and taxifolin, on the other hand, gave docking energies comparable to zearalenone with ERβ (−106.0, −104.6, and −104.5 kJ/mol, respectively), and these flavonoids have also shown estrogenic activity (Plíšková et al. 2005). Silymarin modulation of ERβ may be responsible for the estrogenic effects of the extract (Seidlová-Wuttke et al. 2003b; Plíšková et al. 2005; El-Shitany et al. 2010).

Tribulus terrestris

Tribulus terrestris has been used to contribute to physical and sexual strength (De Combarieu et al. 2003; Neychev and Mitev 2005). The plant is rich in steroidal glycosides (Wu et al. 1996; Yan et al. 1996; De Combarieu et al. 2003; Dinchev et al. 2008) and T. terrestris extracts have shown androgenic effects in animal models (Gauthaman et al. 2002; Gauthaman and Ganesan 2008), but had no influence on androgen production (Neychev and Mitev 2005) or gains in strength or muscle mass (Rogerson et al. 2007) in young men. To our knowledge, there have been no reports on the estrogenic effects of T. terrestris.

In addition to steroids, several alkaloids (N-trans-feruloyltyramine, perlolyrine, terresoxazine, terrestriamide, tribulusamide A and tribulusamide B) and flavonoids (isorhamnetin, kaempferol, and quercetin) have been found in T. terrestris. In-silico molecular docking has shown that N-trans-feruloyltyramine docks strongly to both ERα and ERβ, perlolyrine docks strongly to ERβ, terrestribisamide docks strongly to ERα, quercetin docks strongly to ERβ, and the steroid 2,3-dihydroxypregn-16-en-20-one docks strongly to both ERα and ERβ.

Trifolium pratense

The alkaloids cis- and trans-clovamide, several coumarins, flavonoids, and isoflavonoids have been identified in red clover (Trifolium pratense). Although there have been no ethnobotanical reports to support it, the presence of isoflavones has led to suggest that red clover may serve as a phytochemical alternative to post-menopausal hormone replacement therapy (Coon et al. 2007). Red clover extract has been shown to exhibit weakly estrogenic effects in a rat model (Burdette et al. 2002) and does show in-vitro ERα and ERβ binding ability (Dornstauder et al. 2001; Beck et al. 2003; Overk et al. 2005). The clinical effectiveness of red clover has not, however, been demonstrated (Fugh-Berman and Kronenberg 2001; Booth et al. 2006).

Biochanin A, daidzein, formononetin, and genistein have been identified as T. pratense isoflavonoids with ERα and ERβ binding activity (Beck et al. 2003; Pfitscher et al. 2008) and these compounds did show a binding preference for ERβ. Molecular docking of these ligands also showed preference for ERβ. They were not, however, the best docking ligands of T. pratense phytochemicals. The alkaloids cis- and trans-clovamide, and the coumarin pratenol B showed good docking to both ERα and ERβ. Of the T. pratense isoflavonoids, calycosin and pseudobaptigenin had more exothermic docking energies to ERβ than did biochanin A, daidzein, formononetin, or genistein.

Trigonella foenum-graecum

Fenugreek (Trigonella foenum-graecum) is used as an antidiabetic (Abdel-Barry et al. 1997) and for lowering blood lipid and cholesterol levels (Prasanna 2000). Phytochemicals identified in T. foenum-graecum include the alkaloid gentianine; the coumarins 7-acetoxy-4-methylcoumarin, trigocoumarin, and trigoforin; the flavonoids 2″-O-p-coumaroylvitexin, 2″-O-p-coumaroylorientin, 6,8-digalactosylapigenin, 8-galactopyranosyl-6-quinovopyranosylapigenin, 8-β-D-galactopyranosyl-6-β-D-xylopyranosylapigenin, isoorientin, isovitexin, kaempferol, luteolin, neocorymboside, orientin, quercetin, trigraecum, vicenin 1, vicenin 2, and vicenin 3; the isoflavonoid 3′,5,7-trihydroxy-5′-methoxyisoflavone; p-coumaric acid; and the steroids 25R-spirosta-3,5-diene (= Δ3,5-deoxyneotigogenin), diosgenin, furostane-2,3,22,26-tetrol (= trigoneoside aglycone), gitogenin, neotigogenin, tigogenin, and yamogenin. Quercetin and 3′,5,7-trihydroxy-5′-methoxyisoflavone were the strongest docking ligands for ERβ. Fenugreek seed extract has shown estrogenic activity (Sreeja et al. 2010).

Turnera aphrodisiaca (syn. T. diffusa)

Damiana leaf has been used in traditional medicine in Neotropical cultures as a stimulant and aphrodisiac (Morton 1981), and the herb is marketed as a sexual enhancer for men and women. Extracts of T. aphrodisiaca have shown aphrodisiac activity in mouse (Helmrick and Reiser 2000; Kumar et al. 2009) and rat (Estrada-Reyes et al. 2009; Estrada-Reyes et al. 2013) models, as well as anxiolytic activity in mice (Kumar and Sharma 2005). Phytochemical investigations have revealed damiana to be rich in flavonoids, including acacetin, apigenin, gonzalitosin, laricitrin, luteolin-8-propenoic acid, orientin, orientin-3″-ketone, pinocembrin, and syringetin (Piacente et al. 2002; Zhao et al. 2007). The extract has shown anti-aromatase (due primarily to acacetin and pinocembrin) and estrogenic activity (due primarily to apigenin, Z-echinacin, and pinocembrin) (Zhao et al. 2008). In contrast to these experimental results, molecular docking revealed the strongest docking Turnera compound to be luteolin-8-propenoic acid (−113.1, −123.1 kJ/mol for ERα and ERβ, respectively) but this compound was inactive in the aromatase and estrogen assays. In contrast, pinocembrin, which was active in both experimental assays, had ERα and ERβ docking energies of −81.4 and −87.9 kJ/mol, respectively.

Vitex agnus-castus

Vitex agnus-castus, “chaste tree”, has been used as a tonic for female reproductive disorders, including menstrual disorders (amenorrhea, dysmenorrhea), premenstrual syndrome (PMS, corpus luteum insufficiency, hyperprolactinemia, infertility, menopause, and disrupted lactation (Daniele et al. 2005; van Die et al. 2013). V. agnus-castus extracts contain several flavonoids (casticin, isoorientin, 6″-caffeoylisoorientin, 6″-caffeoylisoorientin-4″-methyl ether, isovitexin, luteolin, orientin, santin, 5-O-demethyltangeretin, and vitexin), diterpenoids (8,14-labdadiene-6,7,13-triol-6,7-diacetate, viteagnuside A, viteagnusin A, viteagnusin B, viteagnusin D, viteagnusin E, viteagnusin F, viteagnusin G, viteagnusin H, viteagnusin I, viteagnusin J, and vitexlactam A), the isoflavonoid vitexcarpan, and the phenolic compounds agnucastoside C and agnuside. Based upon docking energies with ERβ, casticin, santin, vitexcarpan, and the aglycones of agnucastoside C and agnuside, could be expected to exhibit ER modulation. Indeed, V. agnus-castus extracts have been shown to bind to ERα (Liu et al. 2001) and ERβ (Jarry et al. 2003). It has been suggested that V. agnus-castus is a source of 3-ketosteroids with progesterone-like activity (Bruneton 1999; Dweck 2006).

Conclusions

This molecular docking study has revealed that almost all popular herbal supplements contain phytochemical components that may bind to the human estrogen receptor and exhibit selective estrogen receptor modulation. As such, these herbal supplements may cause unwanted side effects related to estrogenic activity. For example, estrogenic agents may be effective and potent growth stimulators of estrogen-receptor positive tumors and pose a hazard to patients with breast cancer who have ER-positive tumors and who are being treated with antiestrogens.

The strongest docking (most exothermic docking energies) phytochemical ligands were phenolic compounds and the weakest docking ligands were triterpenoids. A common binding motif for phenolic ligands in ERα is the hydrophobic pocket of Leu 387, Phe 404, Met 388, and Leu 391, along with edge-to-face π–π interactions with Phe 404, and hydrogen bonds between the phenolic –OH group and the guanidine group of Arg 394 and the carboxylate of Glu 356. Similarly, interactions of phenolic ligands with ERβ include binding in a hydrophobic pocket formed by Leu 298, Leu 339, and Phe 356; edge-to-face π–π interactions of the phenolic ligand with Phe 356 and hydrogen boding of the phenolic –OH group with the carbonyl group of Leu 339, the guanidine group of Arg 346, and the carboxylate of Glu 305. Common hydrogen-bonding residues in the binding sites of ERα are the guanidine group of Arg 394, the imidazole group of His 524. Hydrogen-bonding residues of ERβ are Arg 346, His 475.

There are several limitations to these docking results:
  • Some of the herbal phytochemicals examined may not be bioavailable due to limited solubility, membrane permeability;

  • This docking study has only examined docking of the natural ligands (or their aglycones) and does not take into account in-vivo hydrolysis or other metabolic derivatization;

  • The docking studies do not account for synergism in the estrogen receptor binding;

  • The molecular docking method itself suffers from inherent limitations (e.g., the protein is modeled as a rigid structure without flexibility, solvation of the binding site and the ligand is excluded, and free-energy estimation of protein-ligand complexes is largely ignored) (Yuriev et al. 2011; Yuriev and Ramsland 2013).

  • Docking energies do not provide information about whether strongly binding ligands may function as agonists or antagonists of the estrogen receptor.

Abbreviations

ERα: 

Estrogen receptor α

ERβ: 

Estrogen receptor β

ER+: 

Estrogen receptor positive

MMFF: 

Merck molecular force field

PDB: 

Protein data bank

PMS: 

Pre-menstrual syndrom

RMSD: 

Root mean square deviation

SERM: 

Selective estrogen receptor modulator

Declarations

Acknowledgments

CNP is grateful to the University of Alabama in Huntsville Department of Chemistry for an undergraduate summer research fellowship.

Authors’ Affiliations

(1)
Department of Chemistry, University of Alabama in Huntsville

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