IN SILICO SCREENING OF POTENTIAL CINNAMIC ACID COMPOUND FROM

CINNAMOMUM BURMANII AS ANTIDIABETIC

Sulfahri1, Moh Rizki Lamatenggo2, Rani Youningsih3 dan Astri Dwi Anugrah 4

Mahasiswa Program Studi Ilmu Biomedik,

Sekolah Pascasarjana,Universitas Hasanuddin,
Jl. Perintis Kemerdekaan No.Km. 10, Tamalanrea Indah, Kec. Tamalanrea, Kota Makassar, Sulawesi Selatan 90245

ABSTRACT: Diabetes mellitus is a group of complex metabolic diseases characterized by a state

of hyperglycemia, namely increased blood sugar levels beyond normal levels. One of them has been found
a family of plants that have antidiabetic activity, one of which is Cinnamomum zeylanicum cinnamon.
Meanwhile, in Indonesia, cinnamon species found include Cinnamomum burmannii which also has
hypoglycemic activity. Cinnamic acid or 3-phenyl-2-propenoic acid or β-phenylacrilic acid is a compound
derived from the isolation of cinnamon bark (Cinnamomum burmanni) from the Lauraceae family. Drug
likeness from ligands was defined based on SwissADME physicochemical properties, which
describes a molecular weight, LogP value, number of H-bond donor and H-bond acceptor,
rotatable bond, and Total Polar Surface Area (TPSA) from ligands. In the result ADMET predict
profile were found Absorption, Distribution, Metabolism, Elimination, and Toxicity from ligan
(Cinnamic acid). Cinnamic Acid showed interaction with hiAPP with binding affinity was -5,3
kkal/mol. In the interaction between glibenclamide with hiAPP, showed binding affinity -3,1
kkal/mol. Cinnamic acid is an alternative treatment for DM.
Key word: Cinnamic Acid, diabetes mellitus, anti-diabetic
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INTRODUCTION
Diabetes mellitus is a group of these drugs can cause serious side effects,
complex metabolic diseases characterized by including hypoglycemia, liver toxicity,
a state of hyperglycemia, namely increased weight gain, physiconia (stomach
blood sugar levels beyond normal levels enlargement), and lactic acidosis. Therefore,
(Emilda, 2018). Type 2 diabetes is the type of efforts are made to find alternative herbal
DM that most often affects people, medicines as a substitute for chemical drugs.
characterized by insulin resistance and β-cell WHO also recommends the use of traditional
damage (FDA, 2008). Many oral antidiabetic medicine including for the maintenance,
drugs are available for the treatment and prevention and treatment of public health,
control of Type 2 DM, such as sulfonylurea especially chronic diseases, degenerative
agents, biguanides (metformin), diseases and cancer.
thiazolidinediones (TZD), α-glucosidase
Many studies have been carried out to
inhibitors, and glucagon-like peptide-1
explore active substances in plants. One of
(GLP-1) inhibitors. However, according to
them has been found a family of plants that
Chattopadhyay (2009) in Fadillah (2014)
have antidiabetic activity, one of which is
Cinnamomum zeylanicum cinnamon. However, the interaction mechanism that
Meanwhile, in Indonesia, cinnamon species occurs between cinnamic acid compounds
found include Cinnamomum burmannii and cysteine protease targets is still unknown.
which also has hypoglycemic activity The purpose of this study was to investigate
(Handayani and Ahmad, 2006). the potential and mechanism of in-silico
molecular inhibition of cinnamic acid
Other cinnamic acid derivatives are
compounds which are better than common
caffeic acid, cinamide, cinnamyl ester and
diabetes drugs. The approach used in this
cinnamic hydrazid. The compounds derived
study included: physicochemical analysis of
from cinnamic acid, both natural and
cinnamic acid compounds based on
synthetic, have been tested for anticancer.
Quantitative Structure–Property
Cinnamic acid and several of its derivatives
Relationship, (QSPR), which is a method of
have been examined as good inhibitors of
comparing the structural characteristics of
AKR1C3 activity. AKR1C3 is a cancer cell
cinnamic acid with its derivatives to
formed in the presence of hormones, such as
determine how similar their bioactivity
prostate cancer, breast cancer and
abilities are based on structural similarities;
endometrial cancer.
and molecular docking analysis, to determine
Ping et al (2010) stated that cinnamon
the interaction affinity of cinnamic acid
oil has an antidiabetic effect, in rats, while the
compounds and their derivatives to target
components contained in cinnamon oil are
proteins from diabetes. In silico, the two
cinnamic acid (42-75%), sinamyl acetate,
analytical methods are excellent synergy
karyofilen, linalool, eugenol (Prasetya and
methods for screening antidiabetic drug
Ngadiwiyana. 2006); and (Jakhetia et al.,
candidates.
2011).
Cinnamic acid or 3-phenyl-2-
propenoic acid or β-phenylacrilic acid with
Molecular Weight is 148.16, molecules
formulas is C9H8O2 is a compound derived
from the isolation of cinnamon bark
(Cinnamomum burmanni) from the
Lauraceae family. Cinnamic acid is used as a
preservative, food flavoring, cosmetics,
soaps and other medicines (Jeffry et al.,
2014). In addition, cinnamic acid can inhibit
Caco-2 cell proliferation and has an
antibacterial effect on Neurospora crassa
(Neves, 2005).
RESEARCH METHODS RESULT
Data Mining • Protein hiAPP
hiAPP receptor (Protein) structures
were taken from the database RCSB PDB
(https://www.rcsb.org/). While the ligand
structures of cinnamate acid and ligand
control (glibenclamide) were retrieved from
PubChem.com. Protein structures were
downloaded in .pdf format and ligands in .sdf
format.
Drug Likeness and Toxicity Analysis of
Ligands
• Protein hiAPP+ligand (Cinnamic
Drug likeness from ligands was
Acid)
defined based on SwissADME
physicochemical properties, which describes
a molecular weight, LogP value, number of
H-bond donor and H-bond acceptor, rotatable
bond, and Total Polar Surface Area (TPSA)
from ligands. In the result ADMET predict
profile were found Absorption, Distribution,
Metabolism, Elimination, and Toxicity from
ligan (Cinnamate acid).
Molecular Docking
PyMOL was used to optimize protein
and ligands. Then, the molecular docking
process was performed using PyRX
application to find binding affinity from
ligand and protein.
Analysis and Visualization
The molecular docking results from
protein and ligands were analyzed and
vizualizate using PyRx. Were found the
binding from protein-ligand (active
compound), protein-control ligand, and
comparison of the ligand binding sites of the
active compounds and control ligand.
 • Protein hiAPP + Glibenclomide hiAPP_Cinnamic
acid -4.9 19.103 18.095
hiAPP_Cinnamic
acid -4.8 5.923 2.839
• Binding Afinity hiAPP +
glibenclomide (Ligan Control)
Binding
Ligand Affinity rmsd/ub rmsd/lb
hiAPP_glibenclomide -3.1 0 0
hiAPP_glibenclomide -1.1 2.139 1.618

• Toxicity of Cinnamic Acid

• Protein hiAPP + (ligan cinnamic Model Result Probabilit

acid + ligan control glibenclomide) y
Absorption
Blood-Brain
BBB+ 0.9526
Barrier
Human
Intestinal HIA+ 0.9945
Absorption
Caco-2
Caco2+ 0.9097
Permeability
P-
Non-
glycoprotein 0.8286
substrate
Substrate
P-
• Binding Affinity of hiAPP + Non-
glycoprotein 0.9861
Sinnamic Acid (Ligan) inhibitor
Inhibitor
Non-
0.9906
inhibitor
Binding
Ligand Affinity rmsd/b rmsd/b Renal
hiAPP_Cinnamic Organic Non-
0.9145
acid -5.3 0 0 Cation inhibitor
hiAPP_Cinnamic Transporter
acid -5.3 5.097 3.57 Distribution
hiAPP_Cinnamic
acid -5.2 8.567 4.685 Subcellular Plasma
0.5803
hiAPP_Cinnamic localization membrane
acid -5.1 23.584 21.553 Metabolism
hiAPP_Cinnamic CYP450 2C9 Non-
acid -5 20.113 18.513 0.7768
Substrate substrate
hiAPP_Cinnamic
acid -5 4.879 3.525 CYP450 2D6 Non-
0.9644
hiAPP_Cinnamic Substrate substrate
acid -5 24.383 23.329 CYP450 3A4 Non-
0.8188
Substrate substrate
 CYP450 1A2 Non- Non-
0.8383 0.9899
Inhibitor inhibitor inhibitor
CYP450 2C9 Non- AMES Non AMES
0.9763 0.9722
Inhibitor inhibitor Toxicity toxic
CYP450 2D6 Non- Non-
0.9546 Carcinogens 0.5927
Inhibitor inhibitor carcinogens
CYP450 Fish Toxicity High FHMT 0.8969
Non-
2C19 0.9724 Tetrahymena
inhibitor
Inhibitor Pyriformis High TPT 0.9585
CYP450 3A4 Non- Toxicity
0.9702
Inhibitor inhibitor Honey Bee
High HBT 0.7685
CYP Low CYP Toxicity
Inhibitory Inhibitory 0.9687 Ready
Biodegradatio
Promiscuity Promiscuity biodegradab 0.7942
n
Excretion le
Toxicity Acute Oral
III 0.8487
Human Ether- Toxicity
a-go-go- Weak Carcinogenici
0.9620 Non-
Related Gene inhibitor ty (Three- 0.7458
required
Inhibition class)

CONCLUSION an antidiabetic because it has a realitely small

The purpose of this study was to
investigate the potential and mechanism of
in-silico molecular inhibition of cinnamic
acid compounds which are better than
common diabetes drugs. Binding Affinity is
"Energy needed by active compounds to bind
to proteins in the body." The smaller the
energy needed, the better the compound is.
Cinnamic Acid showed interaction
with hiAPP with binding affinity was -5,3
kkal/mol. In the interaction between
glibenclamide with hiAPP, showed binding
affinity -3,1 kkal/mol. Based on the results, I
can be cocluded that cinnamic acid from
Cinnamon burmani plant has a greater
binding affinity than glibenclimide as ligand
control, therefor glibenclamide is better such
as a diabetic drug than cinnamic acid.
However, cinnamic acid can also be used as
binding affinity.
REFERENCES
1. Bairwa R, Mariam SD, et al. Novel
molecular hybrid of cinnamic acids
and guanylhidrazones as potential
antitubercular agents. Bioorganic and
Medicinal Chemistry Letters.
2010.20: 1623–25. 246-252
2. Baltas MPDe, Belval FB. Cinnamic acid
derivatives as anticancer agents- A
review. Current Medicinal
Chemistry. 2011.18:1672–1703.
3. Emilda, Efek Senyawa Bioaktif Kayu
Manis Cinnamomum Burmanii Nees
Ex.Bl.) Terhadap Diabetes Melitus:
Kajian Pustaka. JFFI. 2018; 5(1)
4. Ernawati T, Wahyuningrum D, Minarti, neucleophosmin. Int J Biochem Cell
Anita Y, Meilawati L, Lotulung PD. Biol. 2008. (40):1918–29.
Development of raw materials for
10. Muchtaridi, Ikhsan R, Ida M. Kadar metil
drugs by using methyl trans
sinamat dari batang, daun dan
cinnamate isolated from galanga
rimpang tumbuhan laja gowah
(Alpinia malaccensis) as novel
(Alpinia malaccensis (Burm f.))
approaches to drug discovery. In:
dengan GC/MS [skripsi]. Bandung:
The Eijkman Institute Comes of
Fakultas Farmasi Universitas
Age: Vitamins, Genomics, dan
Padjajaran; 2008.
Welfare. Jakarta: Eijkman Institute
for Molecular Biology; 2011. 146. 11. Neves, F .M., Kawano, C.Y., Said, S.,
Effect of benzene compounds from
5. Fadillah RU. Antidiabetic Effect of
plants on the growth and hyphal
Morinda Citrifolia L. As A Treatment
morphology in Neurospora crassa,
of Diabetes Mellitus. 2014. Jurnal
Brazilian Journal of Microbiology,
Majority Volume 3 Nomor 7.
2005, Vol.36 No.2, ISSN 1517-8382
6. Food and Drug Administration. Guidance
12. Ping. H.. Guijun Z. Guixing R.
for Industry Diabetes Mellitus —
Antidiabetic Effects of Cinnamon Oil
Evaluating Cardiovascular Risk in
in Diabetie KK-Ay Mice, Food and
New Antidiabetic Therapies to Treat
Chemical Toxicology, 48. 2010.
Type 2 Diabetes. U.S. Department of
2344-2349
Health and Human Services Food and
Drug Administration Center for Drug 13. Prasetya, N.BA, Ngadiwiyana, 2006,
Evaluation and Research (CDER). Identifikasi Senyawa Penyusun
2008 Minyak Кауи Manis (Сіппаmomun
cassia) Menggunakan GC-MS.,
7. Handayani FW dan Ahmad M. Beberapa
Jurnal Sains dan Matematika, Vol
Tumbuhan Di Indonesia Berpotensi
(14). No.2
Sebagai Alternatif Obat Antidiabetes.
2006. Jurnal Farmaka Volume 4 No 4 14. Sinaga E. Alpinia galanga (L.) Willd.,
Lengkuas. Pusat Penelitian dan
8. Jakhetia, V., Patel, R.. Khatri, P. Pahuja,
Pengembangan Tumbuhan Obat
N.. Garg. S.. Pdaney. A.. Sharma, S.,
UNAS (P3TO UNAS). Diambildari
Cinnamon A Pharmalogical Review,
URL:http://www.warintek.ristek.go.
Journal of Advanced Scientific
id/pangan_kesehatan/tanaman_obat/
Research. Vol 1(2), 2010. pp. 19-23
depkes/Bunglai%20laki.pdf. diakses
9. Li QF, Shi SL, Liu QR, Tang J, Song J, tanggal 24 Nov 2022.
Liang Y. Anticancer effects of
ginsenoside Rg1, cinnamic acid and
tanshinone in osteosarcoma MG-63
cells: Down regulation and
cytoplasmic trafficking of