Sains Malaysiana 52(12)(2023): 3497-3509
http://doi.org/10.17576/jsm-2023-5212-12
Molecular
Mechanism of DLBS3233 Bioactive Fraction in Type-2 Diabetes Mellitus: Network
Pharmacology and Docking Study
(Mekanisme Molekul Pecahan Bioaktif DLBS3233 dalam Diabetes
Mellitus Jenis-2: Farmakologi Rangkaian dan Kajian Dok)
SANTI
TAN1,2, RAYMOND RUBIANTO TJANDRAWINATA1,* & VIVITRI DEWI PRASASTY3
1Faculty
of Biotechnology, Atma Jaya Catholic University of
Indonesia, South Jakarta, DKI Jakarta 12930,
Indonesia
2Bioinformatics
and Computational Biology, Dexa Group, South
Tangerang, Banten 15224, Indonesia
3Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton
Rouge, Louisiana 70803, United States
Diserahkan: 5 April 2023/Diterima: 1 Disember 2023
Abstract
Although
several antidiabetic agents are currently available, they commonly have
undesirable effects and are not fully effective in reducing blood glucose.
Therefore, since a long time ago, some Indonesians have preferred herbal
medicine to cure and prevent diseases such as Lagerstroemia speciosa (L.) Pers. and Cinnamomum burmanni. (Nees & T.Nees) Blume, plants
from Indonesia, are believed to be able to treat type 2 diabetes mellitus
(T2DM). Both herbs are present in DLBS3233 bioactive fraction, a standardized
herbal extract that acts as an insulin sensitizer like thiazolidinediones (TZDs). However, the molecular mechanisms, the
bioactive compounds, and the target proteins involved remain unclear. To
understand more about the potential molecular mechanism of DLBS3233 in treating
T2DM, this network pharmacology study is conducted for the first time.
Quercetin, kaempferol, and ellagic acid were discovered to have antidiabetic effects in this study as selected
compounds of DLBS3233, primarily on eight core target proteins, including AKT1,
EGFR, GSK3B, IL6, PTK2, RELA, SRC, and VEGFA. We also found that they exhibited
ligand-receptor binding activity comparable to pioglitazone in the molecular
docking study. Concisely, as a reference for furthering the development of this
bioactive fraction, this study provides novel information on DLBS3233 in T2DM
treatment that was not shown in prior studies.
Keywords: Cinnamomum burmanni. Blume; DLBS3233; Lagerstroemia speciosa; network pharmacology; type 2 diabetes mellitus
Abstrak
Walaupun beberapa agen antidiabetik kini tersedia, agen tersebut biasanya mempunyai kesan yang tidak diingini dan tidak berkesan sepenuhnya dalam mengurangkan glukosa darah. Oleh itu, sejak dahulu lagi, sebilangan masyarakat Indonesia lebih menggemari jamu bagi mengubati dan mencegah penyakit seperti Lagerstroemia speciosa (L.) Pers. dan Cinnamomum burmanni. (Nees & T.Nees) Blume, tumbuhan dari Indonesia, dipercayai mampu merawat diabetes mellitus jenis 2 (DMJ2). Kedua-dua herba hadir dalam pecahan bioaktif DLBS3233, ekstrak herba piawai yang bertindak sebagai pemeka insulin seperti thiazolidinediones (TZDs). Walau bagaimanapun, mekanisme molekul, sebatian bioaktif dan protein sasaran yang terlibat masih tidak jelas. Untuk memahami lebih lanjut mengenai potensi mekanisme molekul DLBS3233 dalam merawat DMJ2, kajian farmakologi rangkaian ini dijalankan buat kali pertama. Kuersetin, kaempferol dan asid elagik didapati mempunyai kesan antidiabetis dalam kajian ini sebagai sebatian terpilih DLBS3233, terutamanya pada lapan protein sasaran teras, termasuk AKT1, EGFR, GSK3B, IL6, PTK2, RELA, SRC dan VEGFA. Kami juga mendapati bahawa mereka menunjukkan aktiviti mengikat reseptor ligan yang setanding dengan pioglitazone dalam kajian dok molekul. Secara ringkas, sebagai rujukan untuk melanjutkan pembangunan pecahan bioaktif ini, kajian ini menyediakan maklumat baru mengenai DLBS3233 dalam rawatan DMJ2
yang tidak didedahkan dalam kajian terdahulu.
Kata kunci: Cinnamomum burmanni. Blume; diabetes mellitus jenis 2; DLBS3233; farmakologi rangkaian; Lagerstroemia speciosa
RUJUKAN
Abbas, A., Agusta, M.K., Dipojono,
H.K., Saputro, A.G., Rachmawati,
H. & Ismaya, W.T. 2018. Preliminary insight into
recognizing of mannose toward LSMT protein: Molecular docking and DFT study. Journal
of Applied and Physical Sciences 4(3): 95-100.
Afendi,
F.M., Okada, T., Yamazaki, M., Hirai-Morita, A., Nakamura, Y., Nakamura, K.,
Ikeda, S., Takahashi, H., Altaf-Ul-Amin,
M., Darusman, L.K., Saito, K. & Kanaya, S. 2012. KNApSAcK family
databases: Integrated metabolite-plant species databases for multifaceted plant
research. Plant Cell Physiol. 53(2): e1.
Ahmed,
H.A., Bhattacharyya, D.K. & Kalita, J.K. 2015.
Core and peripheral connectivity-based cluster analysis over PPI network. Computational
Biology and Chemistry 59(12): 32-41.
Al-Dhubiab, B.E. 2012. Pharmaceutical applications and
phytochemical profile of Cinnamomum burmannii. Pharmacognosy Reviews 6(12): 125-131.
Arozal,
W., Louisa, M. & Soetikno, V. 2020. Selected
Indonesian medicinal plants for the management of metabolic syndrome: Molecular
basis and recent studies. Frontiers in Cardiovascular Medicine 7: 82.
Bader,
G.D. & Hogue, C.W.V. 2003. An automated method for finding molecular
complexes in large protein interaction networks. BMC Bioinformatics 4:
2.
Bai,
N., He, K., Roller, M., Zheng, B., Chen, X.Z., Shao, Z.G., Peng, T.S. &
Zheng, Q.Y. 2008. Active compounds from Lagerstroemia speciosa,
insulin-like glucose uptake-stimulatory/inhibitory and adipocyte
differentiation inhibitory activities in 3T3-L1 cells. Journal of
Agricultural and Food Chemistry 56(24): 11668-11674.
Berman,
H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig,
H., Shindyalov I.N. & Bourne, P.E. 2000. The
protein data bank. Nucleic Acids Research 28: 235-242.
Chen,
E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R. & Ma'ayan,
A. 2013. Enrichr: Interactive and collaborative HTML5
gene list enrichment analysis tool. BMC Bioinformatics 14: 128.
Daina,
A., Michielin, O. & Zoete,
V. 2019. SwissTargetPrediction: Updated data and new
features for efficient prediction of protein targets of small molecules. Nucleic
Acids Research 47(W1): W357-W364.
Daina,
A., Michielin, O. & Zoete,
V. 2017. SwissADME: A free web tool to evaluate
pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small
molecules. Scientific Reports 7: 42717.
Delaney,
J.S. 2004. ESOL: Estimating aqueous solubility directly from molecular
structure. Journal of Chemical Information and Computer Sciences 44(3):
1000-1005.
Fasshauer,
M. & Paschke, R. 2003. Regulation of adipocytokines and insulin resistance. Diabetologia 46(12): 1594-1603.
Feng,
W.W., Ao, H., Yue, S.J. & Peng, C. 2018. Systems
pharmacology reveals the unique mechanism features of Shenzhu capsule for treatment of ulcerative colitis in comparison with synthetic drugs. Scientific Reports 8: 16160.
Gottlieb,
A., Stein, G.Y., Oron, Y., Ruppin,
E. & Sharan, R. 2012. INDI: A computational
framework for inferring drug interactions and their associated recommendations. Molecular Systems Biology 8: 592.
Haq,
F.U., Siraj, A., Ameer, M.A., Hamid, T., Rahman, M.,
Khan, S., Khan, S. & Masud, S. 2021. Comparative
review of drugs used in diabetes mellitus - new and old. Journal of Diabetes
Mellitus 11(4): 115-131.
Hastings,
J., Owen, G., Dekker, A., Ennis, M., Kale, N., Muthukrishnan,
V., Turner, S., Swainston, N., Mendes, P. &
Steinbeck, C. 2016. ChEBI in 2016: Improved services
and an expanding collection of metabolites. Nucleic Acids Res. 44(D1):
D1214-D1219.
Jia,
C.C., Pan, X.C., Wang B.Y., Wang, P.Y., Wang, Y.W. & Chen, R. 2021.
Mechanism prediction of Astragalus membranaceus against cisplatin-induced kidney damage by
network pharmacology and molecular docking. Evidence-Based Complementary and
Alternative Medicine 2021: 9516726.
Jonas,
M.I., Kurylowicz, A., Bartoszewicz,
Z., Lisik, W., Jonas, M., Domienik-Karlowicz,
J. & Puzianowska-Kuznicka, M. 2017. Adiponectin/resistin interplay in serum and in adipose tissue of obese
and normal-weight individuals. Diabetology & Metabolic Syndrome 9: 95.
Kanehisa,
M. 2000. Post-Genome Informatics. Oxford: Oxford University Press.
Kassi,
E., Pervanidou, P., Kaltsas,
G. & Chrousos, G. 2011. Metabolic syndrome:
Definitions and controversies. BMC Medicine 9: 48.
Keiser,
M.J., Roth, B.L., Armbruster, B.N., Ernsberger, P., Irwin, J.J. & Shoichet,
B.K. 2007. Relating protein pharmacology by ligand chemistry. Nat Biotech 25(2): 197-206.
Ko,
S.H., Hur, K.Y., Rhee, S.Y., Kim, N.H., Moon, M.K.,
Park, S.O., Lee, B.W., Kim, H.J., Choi, K.M. & Kim J.H. 2017. Antihyperglycemic agent therapy for adult patients with
type 2 diabetes mellitus 2017: A position statement of the Korean diabetes
association. The Korean Journal of Internal Medicine 32(6): 947-958.
Li,
F., Duan, J.L., Zhao, M.N., Huang, S.J., Mu, F., Su,
J., Liu, K., Pan, Y., Lu, X.M., Li, J., Wei, P.F., Xi, M.M. & Wen, A. 2019.
A network pharmacology approach to reveal the protective mechanism of Salvia miltiorrhiza-Dalbergia odorifera coupled-herbs on coronary heart
disease. Scientific Reports 9: 19343.
Lin,
Y.X., Shen, C.Q., Wang, F.J., Fang, Z.H. & Shen, G.M. 2021. Network
pharmacology and molecular docking study on the potential mechanism of Yi-Qi-Huo-Xue-Tong-Luo formula in
treating diabetic peripheral neuropathy. Journal of Diabetes Research 2021: 9941791.
Lipinski,
C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J.
2001. Experimental and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Advanced Drug
Delivery Reviews 46(1-3): 3-26.
Liu,
Y., Grimm, M., Dai, W.T., Hou, M.C., Xiao, Z.X. &
Cao, Y. 2020. CB-Dock: A web server for cavity detection-guided protein–ligand
blind docking. Acta Pharmacologica Sinica 41(1): 138-144.
Manaf,
A., Tjandrawinata, R.R. & Malinda, D. 2016.
Insulin sensitizer in prediabetes: A clinical study with DLBS3233, a combined
bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa. Drug Design, Development, and Therapy 10(3): 1279-1289.
Maximus,
P.S., Al Achkar, Z., Hamid, P.F., Hasnain,
S.S. & Peralta, C.A. 2020. Adipocytokines: Are
they the theory of everything? Cytokine 133: 155144.
Mohanraj,
K., Karthikeyan, B.S., Vivek-Ananth,
R.P., Bharath Chand, R.P., Aparna,
S.R., Mangalapandi, P. & Samal,
A. 2018. IMPPAT: A curated database of Indian medicinal plants, phytochemistry, and therapeutics. Scientific Reports 8: 4329.
Nailufar,
F., Tandrasasmita, O.M. & Tjandrawinata,
R.R. 2011. DLBS3233 increases glucose uptake by mediating upregulation of PPARγ and PPARδ expression. Biomedicine & Preventive Nutrition 1(2): 71-78.
Nurcahyanti,
A., Arieselia, Z., Kurniawan,
S., Sofyan, F. & Wink, M. 2018. Revisiting bungur (Lagerstroemia speciosa)
from Indonesia as an antidiabetic agent, its mode of action and phylogenetic
position. Pharmacognosy Reviews 12(23):
40-45.
Okamoto,
Y., Kihara, S., Funahashi,
T., Matsuzawa, Y. & Libby, P. 2006. Adiponectin: A key adipocytokine in metabolic syndrome. Clinical Science 110(3): 267-278.
Perkumpulan Endokrinologi Indonesia. 2021. Pedoman Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 Dewasa di Indonesia –
2021. Jakarta: PB PERKENI.
Permadi,
W., Hestiantoro, A., Ritonga,
M.A., Ferrina, A.I., Iswari,
W.A., Sumapraia, K., Muharram, R., Djuwantono, T., Wiweko, B. & Tjandrawinata, R.R. 2021. Administration of cinnamon and Lagerstroemia speciosa extract on lipid profile of polycystic
ovarian syndrome women with high body mass index. Journal of Human
Reproductive Sciences 14(1): 16-20.
Pessin,
J.E. & Saltiel, A.R. 2000. Signaling pathways in
insulin action: Molecular targets of insulin resistance. The Journal of
Clinical Investigation 106(2): 165-169.
Pettersen,
E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C. & Ferrin, T.E.
2004. UCSF Chimera--a visualization system for exploratory research and
analysis. J. Comput. Chem. 25(13): 1605-1612.
Priyadi,
A., Permana, H., Muhtadi,
A., Sumiwi, S.A., Sinuraya,
R.K. & Suwantika, A.A. 2021. Cost-effectiveness
analysis of type 2 diabetes mellitus (T2DM) treatment in patients with
complications of kidney and peripheral vascular diseases in Indonesia. Healthcare 9(2): 211.
Rahardjo,
N.W., Ramdani, E.D. & Tjandrawinata,
R.R. 2020. Metabolomic study and in silico approach of DLBS1442 as progesterone receptor
agonist. Journal of Applied Pharmaceutical Science 10(5): 63-69.
Rahman,
M.M., Vadrev, S.M., Magana-Mora, A., Levman, J. & Soufan, O. 2022.
A novel graph mining approach to predict and evaluate food-drug interactions. Scientific
Reports 12: 1061.
Ramdani,
E.D., Yanuar, A. & Tjandrawinata,
R.R. 2019. Comparison of dopamine D2 receptor (homology model and X-ray
structure) and virtual screening protocol validation for the antagonism
mechanism. Journal of Applied Pharmaceutical Science 9(9): 17-22.
Ranjith,
D. & Ravikumar, C. 2019. SwissADME predictions of pharmacokinetics and drug-likeness properties of small molecules
present in Ipomoea mauritiana Jacq. Journal
of Pharmacognosy and Phytochemistry 8(5): 2063-2073.
Rao,
P.V. & Gan, S.H. 2014. Cinnamon: A multifaceted
medicinal plant. Evidence-Based Complementary and Alternative Medicine 2014: 642942.
Serbis,
A., Giapros, V., Kotanidou,
E.P., Galli-Tsinopoulou, A. & Siomou,
E. 2021. Diagnosis, treatment, and prevention of type 2 diabetes mellitus in
children and adolescents. World Journal of Diabetes 12(4): 344-365.
Shahid,
M., Azfaralariff, A., Law, D., Najm,
A.A., Sanusi, S.A., Lim, S.J., Cheah,
Y.H. & Fazry, S. 2021. Comprehensive
computational target fishing approach to identify xanthorrhizol putative targets. Scientific Reports 11: 1594.
Shannon,
P., Markiel, A., Ozier, O., Baliga, N.S., Wang, J.T., Ramage,
D., Amin, N., Schwikowski, B. & Ideker, T. 2003. Cytoscape: A
software environment for integrated models of biomolecular interaction networks. Genome Research 13(11): 2498-2504.
Stelzer,
G., Rosen, R., Plaschkes, I., Zimmerman, S., Twik, M., Fishilevich, S., Iny Stein, T., Nudel, R., Lieder,
I., Mazor, Y., Kaplan, S., Dahary,
D., Warshawsky, D., Guan-Golan, Y., Kohn, A.,
Rappaport, N., Safran, M. & Lancet, D. 2016. The GeneCards Suite: From gene data mining to disease genome
sequence analyses. Current Protocols in Bioinformatics 54:
1.30.1-1.30.33.
Tandrasasmita,
O.M., Wulan, D.D., Nailufar,
F., Sinambela, J. & Tjandrawinata,
R.R. 2011. Glucose-lowering effect of DLBS3233 is mediated through
phosphorylation of tyrosine and upregulation of PPARγ and GLUT4 expression. International Journal of General Medicine 4:
345-357.
The UniProt Consortium. 2021. UniProt:
The universal protein knowledgebase in 2021. Nucleic Acids Research 49(D1): D480-D489.
Tisnadjaja,
D., Irawan, H., Ekawati,
N., Bustanussalam, B. & Simanjuntak,
P. 2020. Potency of Cinnamomum burmannii as antioxidant and α glucosidase
inhibitor and their relation to trans-cinamaldehyde and coumarin contents. Jurnal Fitofarmaka Indonesia 7(3): 20-25.
Tjandrawinata,
R.R., Suastika, K. & Nofiarny,
D. 2012. DLBS3233 extract, a novel insulin sensitizer with negligible risk of
hypoglycemia: A phase-I study. International
Journal of Diabetes and Metabolism 21(4): 13-20.
Tjandrawinata,
R.R., Amalia, A.W., Tuna, H., Said, V.N. & Tan,
S. 2022. Molecular mechanisms of network pharmacology-based immunomodulation of Huangqi (Astragali Radix). Jurnal Ilmu Kefarmasian Indonesia 20(2): 184-195.
Tjokroprawiro,
A., Murtiwi, S. & Tjandrawinata,
R.R. 2016. DLBS3233, a combined bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa,
in type-2 diabetes mellitus patients inadequately controlled by metformin and
other oral antidiabetic agents. Journal of Complementary and Integrative
Medicine 13(4): 413-420.
Verdini,
L., Setiawan, B., Sinaga,
T., Sulaeman, A. & Wibawan,
W.T. 2020. Phytochemical profile of cinnamon extract (Cinnamomum burmanii Blume) from three regions of Sumatra
Island using GCMS. European Journal of Molecular & Clinical Medicine 7(2): 4557-4568.
Wiweko,
B. & Susanto, C.A. 2017. The effect of metformin
and cinnamon on serum anti-mullerian hormone in women
having PCOS: A double-blind, randomized, controlled trial. Journal of Human
Reproductive Sciences 10(1): 31-36.
Zhang,
Y.F., Jiang, W.L., Xia, Q.Q., Qi, J. & Cao, M.S. 2019. Pharmacological
mechanism of Astragalus and Angelica in
the treatment of idiopathic pulmonary fibrosis based on network pharmacology. European
Journal of Integrative Medicine 32: 101003.
Zhou,
P., Zhou, R., Min, Y., An, L.P., Wang, F. & Du, Q.Y. 2022. Network pharmacology
and molecular docking analysis on pharmacological mechanisms of Astragalus membranaceus in the treatment of gastric ulcer. Evidence-Based Complementary and
Alternative Medicine 2022: 9007396.
*Pengarang untuk surat-menyurat;
email: raymond@dexa-medica.com
|