Annals of Medicine and Surgery 67 (2021) 102459
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Annals of Medicine and Surgery
journal homepage: www.elsevier.com/locate/amsu
Experimental Research
IN-SILICO dynamic analysis of Sulawesi propolis as anti-endometriosis
drug: Interaction study with TNF alpha receptor, NF-kB, estrogen receptor,
progesterone receptor and prostaglandin receptor
Herbert Situmorang a, *, Andon Hestiantoro a, Sigit Purbadi a, Darin Flamandita b,
Muhamad Sahlan b
a
Department of Obstetrics and Gynecology Faculty of Medicine Universitas Indonesia – Dr Cipto Mangunkusumo National Referral Hospital, Jl. Salemba Raya No. 6,
Central Jakarta, Jakarta Capital Special Region, 10430, Indonesia
b
Department of Chemical Engineering, Faculty of Engineering, Universitas Indonesia, Jl. Fuad Hasan, Pancoran MAS, Kukusan, Beji, Depok City, West Java, 16424,
Indonesia
A R T I C L E I N F O
A B S T R A C T
Keywords:
Docking
In silico
Propolis
Endometriosis
TNF alpha Receptor
NF-kB
Estrogen receptor
Progesterone receptor
Prostaglandin receptor
Introduction: Endometriosis is a disease that impacts around 10% of all women in reproductive age, with pelvic
pain and infertility as its main clinical features. Current medical treatment targeting lowering estrogen activity
has not shown sufficient result due its side effects and reproductive function suppression. Propolis has been
widely studied, showing anti inflammation and pro-apoptosis property, that could potentially be used in the
treatment of endometriosis. This study investigates the interaction between Sulawesi Propolis’ active components and receptors and protein related to endometriosis pathogenesis.
Methods: Active components of Sulawesi Propolis were initially identified with their targeted protein receptors.
Lipinski rules were used to screen potential components. The ligands and proteins were tested using Autodock
program to predict the most active compound and possible binding sites between propolis and some target
proteins associated with inflammatory and apoptotic activity in endometriosis models. Receptor modelling is
then performed using Swiss-Model.
Results: These active components of Sulawesi Propolis showed a strong binding potential towards TNF- α, NF-kb,
Estrogen-α, Estrogen-β, progesterone B, PGE2 EP2 and EP3 subtype respectively: Sanggenon C, Sanggenon H,
Epicryptoacetalide, Chrysin-7-O-β-D-glucopyranodside, Irilone, Polydatin and Epicryptoacetalide. Compared to
its negative ligand, Sulawesi Propolis displayed a stronger binding capacity to TNF-α, Estrogen-α, and Progesterone B receptors.
Conclusion: Sulawesi Propolis has the ability to interact with receptors related to reproductive function, apoptotic
reactions and inflammatory processes, a significant factor associated with the pathogenesis of endometriosis.
1. Introduction
Endometriosis found in women of childbearing age is still a big
problem nowadays. With an incidence of around 10% of all female ages,
complaints about chronic pelvic pain and infertility can cause physical,
mental and social problems for patients. However, the current medical
treatment showed unsatisfactory result in overcoming problems, even
aggravating the patient’s suffering due to failure to meet patient
expectations.
The inflammatory reaction to endometrial tissue outside the uterine
cavity causes various problems, especially pelvic pain and subfertility.
Nuclear factor kappa-light-chain-enhancer activated B cells (NF-kB)
pathway increases the expression of inflammatory mediators such as
interleukin (IL) -1B, IL-6, IL-8 and Tumor Necrotizing Factor (TNF)
alpha. The release of these inflammatory mediators accelerates the
prolonged inflammatory process and is responsible for the reduced activity of endometriosis cell apoptosis [1].
Medical treatment targeting single pathogenesis mechanism only,
does not bring satisfactory results. Surgery alone cannot seem to solve
endometriosis without a long-term postoperative treatment strategy to
* Corresponding author.
E-mail address: herbert.situmorang@ui.ac.id (H. Situmorang).
https://doi.org/10.1016/j.amsu.2021.102459
Received 28 April 2021; Received in revised form 24 May 2021; Accepted 26 May 2021
Available online 17 June 2021
2049-0801/© 2021 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
H. Situmorang et al.
Annals of Medicine and Surgery 67 (2021) 102459
prevent the recurrence of this disease [2]. Besides, endometriosis medical treatment is still based on hormonal drugs that suppress the estrogen’s action, as the primary pathway for its various pathogenesis. This
approach results in attenuation of folliculogenesis and ovulation, which
negate the possibility of being conceived during the treatment [3].
Therefore, there is a high urgency in providing endometriosis medication that can be used long-term with minimum side effect, and does not
alter the hypothalamus-pituitary-ovarian pathway.
One of the natural ingredients that has been widely studied for its
health benefits is Propolis. Propolis from Tetragonula aff. biroi originating from Luwu District, South Sulawesi has been investigated to have
anti-oxidant and anti-inflammatory effects as well as to have a proapoptotic effect on various cancer line cells [4]. The effect of the
Propolis active substances, which target various pathogenesis pathways
for endometriosis, has the potential to be used as medical therapy for
endometriosis. However, there is no data on the use of Propolis in
endometriosis. This signifies the importance of research that can prove
the benefits of Propolis Indonesia as a medical treatment in endometriosis that increases apoptotic activity, decreases the inflammatory
activity, and does not interfere with ovulation.
The process of developing drugs from natural ingredients is known
be lengthy (11–16 years) [5]. Thus, to accelerate the process of drug
discovery, a variety of computer software has been used called the
in-silico research model. In investigating its efficacy, an in-silico study
was conducted to determine Propolis active components that can
interact with endometriosis-related receptors such as TNF-alpha, NF-κB,
estrogen, progesterone, and prostaglandin receptors.
and stored as a ligand with PBD (Protein Data Bank) extension. Protein
or receptor model involved in endometriosis pathogenesis, i.e. TNF
alpha receptor, NFĸB receptor protein, estrogen receptor alpha, estrogen
receptor beta, prostaglandin E2 receptor subtype EP2 and EP3 were to
be tested. A receptor modelling using Swiss Model from Uniprot
sequencing was created for receptors whose model is unavailable in
PDB. These ligands and proteins were tested using the standard Lamarckian algorithm in the Autodock program. The binding energies
(ΔG), inhibitor concentration (Ki), hydrogen bond (H-bond) involved in
the ligand-receptor complex formation were determined.
3. Results
Following Lipinski’s rules of five, 22 out of 25 active compounds
from Tetragonula aff. biroi bee colony propolis showed a strong binding
potential with endometriosis-related receptors such as TNF-⍺, NFĸB,
estrogen α, estrogen β, progesterone A, progesterone B, and prostaglandin E2 as shown in Table 1.
All active components of Indonesia propolis showed a high binding
potential (less than 0) to TNF-alpha receptors. This confirms other
studies reported a good anti-inflammatory activity of Indonesia propolis
[7]. Sanggenon C has the highest affinity with ΔG 10.2 KCal/mol, and Ki
0.03 μM. Meanwhile, in the NF-kB, Sanggenon H has the highest affinity
with ΔG 9,8 KCal/mol, and Ki 0.07 μM8.
All active components of Indonesia Propolis showed a good negativedocking score to ER-α, except Sanggenon C, which showed a positive
docking score. Epicryptoacetalide revealed the highest affinity to ER-α
with ΔG 8,9 KCal/mol, and Ki 0.3 μM. Moreover, the highest docking
score affinity to ER-β with ΔG 9,1 KCal/mol, and Ki 0.21 μM was shown
by Chrysin-7-OBD-glucopyranoside [8].
Besides having the highest affinity to TNF-alpha receptor, Sanggenon
C also signified the highest affinity to PR-B with ΔG 10 KCal/mol, and Ki
0.05 μM. Our study in PGE2 receptor (EP3 subtype), elucidated that
Polydatin exhibited the highest affinity with ΔG 10,7 KCal/mol, and Ki
0.01 μM, and finally, Epicryptoacetalide displayed the highest affinity
with ΔG 10,7 KCal/mol, and Ki 0.01 μM to PGE2 receptor (EP2 subtype),
see Table 1.
Docking interactions were grouped to determine the Gibbs energy
(ΔG) since the lower ΔG showed the conformational energy for the best
docking value. Calculation of inhibitor concentration (Ki) was reported
to determine the binding energy produced from docking as shown in
2. Material and methods
The previous study has elucidated the active components of Indonesian Propolis. These compounds are 2-Methoxykurarinone, Kurarinone, Chrysin-7-O-β-D-glucopyranoside, Flavenochromane B, Ginkgol,
Irilone, Leachianone A, Icaritin, Sanggenon C, Scutellarein, Cimicifugic
acid, Demethoxycurcumin, Dendrocandin B, Ricinoleic acid, Polydatin,
Epicryptoacetalide, Caesalpins J, Ginkgetin, Lupinifolin, Rhamnetin,
Sanggenon H, Shogaol, 4- Hydroxy ginkgolic acid, 9,16-Dioxyhydroxy10,12,14-triene-18 carbonic acid, and 4′ -O-Methylbrazilin [6].
Twenty-five compounds in Propolis were tested for screening, predicting which compounds might be developed into drugs using Lipinski’s rule of five. Three-dimensional shapes of compounds were made
Table 1
Docking results (ΔG) of propolis active compounds affinity to receptors associated endometriosis pathogenesis.
No
Active Compounds
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2-methoxykurarinone
Kurarinone
Chrysin-7-O-β-D-glucopyranoside
Flavenochromane B
Ginkgol
Irilone
Leachianone A
Icaritin
Scutellarein
Cimicifugic acid
Demethoxycurcumin
Dendrocandin B
Ricinoleic acid
Polydatin
Sanggenon H
Sanggenon C
Epicryptoacetalide
Shogaol
Caesalpins J
Ginkgetin
Lupinifolin
Rhamnetin
Native ligand
TNF
Alpha
NF-kB
Estrogen
Alpha
Estrogen
Beta
Proges-terone B
PGE2 EP3 Subtype
PGE2 EP2 Subtype
−7,9
−8,−8,8
−9,5
−5,8
−8,2
−8,6
−7,8
−6,8
−7,9
−7,4
−8,1
−5,6
−7,7
−8,8
−10,2
−8,2
−5,8
−7,8
−9,9
−8,8
−7,7
−8.23
−6,5
−6,9
−8,7
−8,4
−5,8
−8,6
−7,1
−7,5
−8,1
−7,9
−7,9
−7,5
−5,4
−7,6
−9,8
−8,7
−8,5
−5,6
−6,8
−8,4
−8,3
−8,7
−6,0
−5,7
−7,7
−8,3
−7,7
−8,3
−6,7
−8,1
−8,2
−6,6
−8,0
−6,9
−7,1
−6,1
−8,3
+5,6
−8,9
−7,0
−8,2
−6,5
−0,8
−8,1
−9,8
−5,1
−6,8
−9,1
−7,5
−7,4
−7,3
−6,1
−6,1
−7,3
−7,5
−7,4
−6,6
−6,9
−6,8
−6,9
−4,9
−7,7
−6,9
−7,0
−7,4
−6,3
−6,9
−7.9
−4,9
−5,1
−6,6
−5,3
−7,5
−10,0
−8,1
−7,2
−8,6
−8,2
−7,7
−6,3
−6,8
−6,2
−8,3
−6,5
−7,9
−6,9
−7,0
−6,0
−6,7
−8,4
−7.9
−8,5
−9,0
−10,3
−5,9
−7,4
−9,3
−9,3
−8,2
−8,4
−9,2
−10,3
−7,2
−6,9
−10,7
−9,2
−5,4
−9,7
−6,5
−6,6
−7,0
−9,0
−9,1
−5,6
−6,0
−7,2
−7,3
−6,3
−7,3
−6,1
−5,6
−6,2
−6,5
−6,3
−6,5
−5,4
−6,1
−7,3
−7,2
−7,8
−5,5
−6,3
−7,0
−6,4
−6,8
−7.96
2
Annals of Medicine and Surgery 67 (2021) 102459
H. Situmorang et al.
Table 2
Summary of docking results, 3D visualization and hydrogen binding site.
Protein Target
Substance with Strongest
Binding Affinity
ΔG in Kcal/
Mol (Ki in
μM)
H Bound
TNF-alpha
Sanggenon C
−10,2 (0,03)
5 (Tyr151(A), Tyr119(B), Ser60(B),
Ser60(B), Leu120(B))
NF-kB p50/p65
Sanggenon H
−9,8 (0,07)
2 (Arg246(A), da18(D))
ER-A
Epicryptoacetalide
−8,9 (0,30)
–
ER-B
Chrysin-7-O-β-Dglucopyranoside
−9,1 (0,21)
4 (Asn234(A), Glu260(A), Val293(A),
Tyr352(A))
Progesterone
Receptor B
Irilone
−10 (0,05)
1 (Tyr151(B))
3D Visualization
(continued on next page)
3
H. Situmorang et al.
Annals of Medicine and Surgery 67 (2021) 102459
Table 2 (continued )
Protein Target
Substance with Strongest
Binding Affinity
ΔG in Kcal/
Mol (Ki in
μM)
H Bound
PGE2 EP3
Polydatin
−10,7 (0,01)
8 (Thr206(A), Tyr114(A), Ser336(A),
Ser336(A), Gln339(A), Gln339(A),
Gly102(A), Thr136(A))
PGE2 EP2
Epicryptoacetalide
−7,8 (1.92)
3D Visualization
–
endometriosis-associated inflammatory responses are dependent on
increased activated macrophages and their secreted cytokines in peritoneal fluid. A local inflammatory microenvironment sustains endometriosis’ growth and maintenance through endometrial-peritoneal
adhesion, invasion, angiogenesis, and proliferation. The inflammatory
process in endometriosis further causes pelvic pain and infertility, two
prominent symptoms of endometriosis.
The use of Propolis in endometriosis treatment has not been studied
extensively. This study elucidates the molecular binding of propolis
components to several targeted proteins known to be essential pathways
of endometriosis. Sulawesi Propolis’ component has been analyzed in
previous studies4. Molecular docking results revealed that the active
components of Sulawesi Propolis have high binding potential to proteins
involved in endometriosis pathophysiology, namely: TNF-alpha receptors, NF-kB p50/p65, estrogen receptors -alpha (ER-α) and -beta (ERβ), progesterone receptor B (PR-B) as well as prostaglandin receptors E2
with EP2 subtype and EP3 subtype.
Nuclear factor kappa-light-chain-enhancer of activated B cells
(NFκB) is known to be one of the most important transcription factors
that facilitate survival and growth of endometriosis cells in addition to
Table 2. Each compound revealed a different conformation which was
correlated with the binding energy value. After determining the active
compound propolis that might show the highest affinity with the receptor related to the pathogenesis of endometriosis, then we made a
receptor modeling in which the propolis compound might be able to
bind to the receptor’s active site.
We utilized the protein complex structure from the protein data bank
in which a compound binds in its receptor active site. The protein
complex exhibited a great box with a center coordinate XYZ and tethering size area where the compounds bind to the receptor. Afterward, we
replaced that compound with the propolis active compound and then
put the propolis active compound to the active binding site as seen in
Table 2. Therefore, when the propolis active compound was bound to
the receptor-associated endometriosis pathogenesis, it was expected can
inhibit the signaling pathway in endometriosis pathogenesis.
4. Discussions
Multiple pathways are involved in endometriosis pathogenesis, in
which chronic inflammation is one of its significant manifestations. The
4
H. Situmorang et al.
Annals of Medicine and Surgery 67 (2021) 102459
the ERK1/2 pathway, and AKT. This NFκB pathway increases the
expression of inflammatory mediators such as interleukin (IL)-1B, IL-6,
IL-8, Regulated on Activation Normal T cell Express and Secreted
(RANTES), Intercellular adhesion molecule (ICAM) 1, Monocyte Chemoattractant Protein (MCP) 1, Cyclooxygenase (COX) 2, Macrophage
migration inhibition (MIF), Matrix Metallo Protein (MMP) 9, and Tumor
Necrosing Factor (TNF). These will trigger a prolonged inflammatory
process in endometriosis cells and surrounding tissue. Besides, this NFκB
pathway is also responsible for the reduced activity of endometriosis cell
apoptosis.
Our study shows that Sanggenon H has the highest docking score to
NF-kB. Sanggenon H has been found in the root of Morus. Morus alba L.
and M. nigra L. (both known as mulberry) - deciduous trees belonging to
the family Moraceae. Their various plant parts have been used in traditional Chinese medicine for centuries. The root bark of M. alba and the
compounds it possesses anti-allergic, anti-inflammatory, antimicrobial,
antioxidant, antiviral, cytotoxic, hypoglycemic, hypolipidemic, and
neuroprotective activities. A study by Zelova et al. that isolates root M.
alba compounds shows that Sanggenon H reduced the activation of NFkB transcription factor [9].
TNF alpha is one of the crucial components in the immune response
of the human organism. Research by Galo et al. determined serum levels
of TNF-alpha in women who underwent laparoscopy or laparotomy due
to pelvic pain, infertility, dysmenorrhoea or pelvic tumors due to
endometriosis [10]. The TNF-alpha level between the endometriotic and
non-endometriotic groups were statistically significant, making it a
newfound non-invasive diagnostic marker for endometriosis. In endometriosis, TNF Alpha binds to TRADD (tumor necrosis factor receptor
type 1-associated death domain protein) that activates the IKK complex
and the NF-kB p50/p65 complex involved in gene transcription that
regulates gene transcription for innate immunity, inflammation, and cell
survival. This process results in a decrease in the ability of apoptosis in
eutopic endometrial cells so that the cells survive [11].
Our study showed that Sanggenon C has the highest affinity to TNF
alpha receptor. The binding of Sanggenon C to the TNF-alpha receptor
induces apoptosis via the TRAIL (Tumor Necrosis Factor Related
Apoptosis Including Ligand) pathway. TRAIL is a part of TNF that
selectively induce apoptosis in cancer cells without causing toxicity to
normal cells. TRAIL induces apoptosis by interacting with cell death
pathways with TRAIL-R1 receptors (death receptor 4-DR4) and TRAILR2 (death receptor)-DR5. Sanggenon C is a well-known active benzopyrone agent of the flavonoid derivative with valuable biological
properties, including anticancer, anti-inflammatory, antimicrobial,
antiviral, antithrombotic, and immune-modulatory activities. A study
conducted by Chen et al. showed that Sanggenon C induces apoptosis of
colon cancer cells by increasing reactive oxygen species generation and
decreasing nitric oxide production, which is associated with inhibition
of inducible nitric oxide synthase expression and activation of mitochondrial apoptosis pathway [12].
Meanwhile, in the NF-kB pathway, the Sanggenon H will bind to the
p50/p65 complex to activate the apoptotic pathway. Sanggenon H is a
prenylated flavonoids which isolated as one of Morus alba (known as
mulberry) root bark compounds [7]. Study by Zelova et al. shows that
Sanggenon H was assigned as nontoxic compounds based on its IC50
values of >10 μM. A review by Wei et al. about bioactive compounds
from root barks of Morus plants (Sang-Bai-Pi) refers that Sanggenon H
inhibited the secretion of TNF-α, IL-1β and NF-kB nuclear translocation
in LPS-stimulated macrophage [13].
Another endometriosis pathogenesis is from the prostaglandin
(PGE2) pathway. PGE2 and activation of its receptors has several effects
on endometriosis pathogenesis: suppressing the macrophage scavenging
capacity, increasing biosynthesis of17-β estradiol (E2) through EP2 receptors, and accelerate cell proliferation through EP3 receptors. When
PGE2 attaches to the EP2 receptor, this process activates adenylyl
cyclase (AC) to make cyclic AMP (cAMP), which then activates protein
kinase A (PKA). Activated PKA translocates to the nucleus and
phosphorylates cAMP responsive element-binding protein (CREB),
which binds to the StAR gene promoter and aromatase. Increased
expression of StAR and aromatase promoter genes induces the production of 17-β estradiol (E2) inside the lesion. By its binding to EP3 receptor PGE2 activates protein kinase Cδ (PKCδ) -Raf-MEK-ERK, which
directly increases FGF9 transcription. Overexpression of FGF9 will
stimulate endometriosis cell proliferation by autocrine and paracrine
regulation [14].
This study showed a successful binding of all active components of
Sulawesi Propolis to EP2 dan EP3 receptors, with Epicryptoacetalide has
the highest ΔG binding to EP2 receptors and Polydatin to EP3 receptors.
Polydatin (PLD), the 3-O-b-glucopyranoside, a well-known stilbenoid
compound resveratrol, is a major compound of Fallopia japonica
(Houtt.) R. Decr. (Japanese knotweed), which is widely used in traditional Chinese medicine to treat infections, inflammatory diseases and
circulatory problems. It is also detected in grapes, peanuts, hop cones,
red wines, hop pellets, cocoa-containing products, chocolate products
and many daily diets [15]. When administered to endometriosis patients, polydatin will be attached to EP2 receptors to activate the
phagocytosis activity which was inhibited by prostaglandin before. It
has shown a wide range of biological activities including
anti-inflammatory, anti-oxidant, anti-cancer, neuroprotective, hepatoprotective, nephroprotective and immunostimulatory effects. It
seems that the mechanisms of the PLD’s beneficial effects are related to
cellular anti-oxidants and anti-inflammatory cascades. De Maria conducted a study investigating whether the Resveratrol (trans-3,5,49-trihydroxystilbene)
and
its
natural
precursors
Polydatin
(resveratrol-3-Ob-mono-D-glucoside, the glycoside form of resveratrol)
combination, might have a cooperative antitumor effect on either
growing or differentiated human adenocarcinoma colon cancer cells. It
showed that the cause of polydatin-induced cell death was apoptosis, as
suggested by activation of caspase-3 cystein protease, acting as a common effector pathway for apoptotic processes originating on both cell
membrane and mitochondrial levels [16].
Estrogen initiates ectopic endometrial growth and changes in estrogen signalling are associated with endometriosis. The source of estradiol, which promotes the growth of ectopic tissue, is not only obtained
from estrogen-producing organs such as the ovaries and adrenals but is
also known to be produced locally by the expression of aromatase in
endometriosis implant. This ectopic endometrial tissue expresses estrogen receptors (ER) α and β differently than eutopic endometrial tissue,
where ERβ is expressed higher. The reduced methylation of the gene
promoter that encodes ERβ is thought to produce excessive expression of
ERβ in endometriosis, which in turn suppresses ERα expression and reduces the formation of progesterone receptors in endometriosis cells
mediated by estradiol. This mechanism contributes to the progesterone
resistance of endometriosis cells, seen by the inactivity of genes mediated by the action of progesterone [14].
Progesterone typically triggers an endometrial response characterized by inhibition of epithelial cell proliferation with apoptotic peaks
when progesterone levels decrease in the two days before menstruation.
Inflammation that occurs in endometriosis can cause progesterone
resistance due to competition or interference by pro-inflammatory
transcription factors. It is mediated by proteins such as the FKBP4 or
Hic-5 companion protein. Progesterone resistance is characterized by a
reduced expression of progesterone B receptors compared to progesterone A receptors [17].
Our finding showed that Irilone has the highest affinity towards
progesterone receptor B. Irilone is an isoflavonoid found in Red Clover
(Trifolium pratense). A study by Lee et al. investigates the use of
botanical dietary supplements. They used a progesterone response
element (PRE)-luciferase (Luc) reporter assay to identify four phytoprogestins present in a standardized red clover (Trifolium pratense)
extract. They found that the component irilone potentiated the effect of
progesterone in both endometrial and ovarian cancer cell lines. In these
cancers, progesterone action is generally associated with positive
5
H. Situmorang et al.
Annals of Medicine and Surgery 67 (2021) 102459
outcomes; thus the potentiating effect of irilone may provide entirely
new strategies for enhancing progesterone signalling as a means of
mitigating conditions such as fibroids and endometriosis [18].
The active compound Epicryptoacetalide of propolis will bind to
alpha estrogen receptors. Limited study has been found on Epicryptoacetalide. One study conducted by Hao et al. examined salvia
plants, one of the ingredients in traditional Chinese medicine. Epicryptoacetalide is one of the ingredients contained in Salvia miltiorrhiza
which is known to have properties in removing blood stasis and
relieving pain, activating blood to promote menstruation, relieving
restlessness; irregular menstruation, amenorrhea, menalgia, mass in the
abdomen, stabbing pain in the chest and abdomen, pyretic arthralgia,
ulcers and sores, sleeplessness, swelling of the liver and spleen, angina
pectoris. But there is no explanation in detail how Epicryptoacetalide
works and what effects it causes [19].
The most active compound of Sulawesi Propolis that binds to beta
estrogen receptors is Chrysin-7-O-β-D-glucopyranoside, as shown in
Table 2. It was found in many plants, such as Calicotome villosa, Halostachys caspica and adenocarpus. An in-silico study conducted by
Nganou et al. on adenocarpus plants to colon cancer cells showed that
chrysin 7-O-β-D-glucopyranoside had good docking results. This means
that chrysin 7-O-β-D-glucopyranoside satisfies all the properties of
pharmacological or biological properties with the best result when
compared with known standards Capecitabine and 5-Fluorouracil in
inhibiting colon cancer cells [20].
Although Sulawesi Propolis showed a strong binding potential towards endometriosis-related receptors, its real biologic effects in endometriosis have not been elucidated by this study. To answer this issue,
dynamic molecular docking or in-vitro/vivo studies are needed. An
animal study is currently carried out to investigate Propolis’ effect on
endometriosis tissue. Only after this then clinical trial in human can be
conducted to evaluate the effect of Sulawesi Propolis and its effective
dosage in endometriosis.
T04374006.
Guarantor
Herbert Situmorang, MD, +62 815-8626-3987, herbert.situmorang
@ui.ac.id.
Consent
We do not have any consent.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no potential conflicting interest in this study.
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5. Conclusion
Sulawesi Propolis active components have a good binding capacity to
several receptors involved in endometriosis pathogenesis. This promising result as the endometriosis drug should be followed by clinical
trials to prove its efficacy as an alternative medication for endometriosis.
Ethical approval
The Ethics Committee of the Faculty of Medicine, University of
Indonesia has approved our study protocol in protocol no. 19-10-1269
with date of approval February 24th, 2020.
Sources of funding
Our study has grant from TADOK 2019 (Tugas Akhir Doktor) from
Universitas Indonesia. The study sponsor had no such involvement in
this study.
Herbert Situmorang: Writing the paper.
Andon Hestiantoro: Study concept.
Sigit Purbadi: Study concept.
Darin Flamandita: Data analysis and interpretation.
Muhamad Sahlan: Study concept.
Registration of research studies
Name of the registry: ClinicalTrials.gov.
Unique Identifying number or registration ID:
ClinicalTrials.gov ID NCT04374006.
Protocol ID 19-10-1269’
Hyperlink to your specific registration (must be publicly accessible
and will be checked): https://clinicaltrials.gov/ct2/show/NC
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