Sains Malaysiana 52(3)(2023): 899-939
http://doi.org/10.17576/jsm-2023-5203-17
Exploration of Annona
muricata (Annonaceae) in the Treatment of Hyperlipidemia
Through Network Pharmacology
and Molecular Docking
(Penerokaan Annona muricata (Annonaceae) dalam
Rawatan Hiperlipidemia Melalui Rangkaian Farmakologi dan Dok Molekul)
RENY SYAHRUNI1,
ABDUL HALIM UMAR1,*, HINDRIYANI NURUL RAHMAN1 & WISNU
ANANTA KUSUMA2
1Division
of Pharmaceutical Biology, College of Pharmaceutical Sciences Makassar (Sekolah
Tinggi Ilmu Farmasi Makassar), Jalan Perintis Kemerdekaan Km. 13.7 Daya,
Makassar 90242, Indonesia
2Department
of Computer Science, Faculty of Mathematics and Natural Sciences, Jalan
Meranti-Dramaga Campus, IPB University, Bogor 16680, Indonesia
Diserahkan: 11 Ogos 2022/Diterima: 5 Januari 2023
Abstract
Soursop (Annona muricata L.) is
one of the plants that have antihyperlipidemic effects, but its underlying mechanism of action remains unknown. Previous
investigations used TCMSP, KNApSAcK, ETCM, SwissTargetPrediction, SuperPred, CTD, and TTD to identify potential targets
of soursop as antihyperlipidemic. Therefore, this study aims to explore soursop active compounds and
demonstrate their mechanisms against hyperlipidemia through network
pharmacology and molecular docking. OB and drug-likeness properties of the compounds from A. muricata were screened based on Lipinski’s Ro5 (Lipinski’s
Rule of Five) parameters. Subsequently, the network of the compound–target–disease–pathways was constructed using Cytoscape. The target PPI
(protein-protein interaction) network was built using STRING and
the core targets were analyzed using GO with KEGG. The main active compounds against the targets were confirmed by molecular
docking analysis. Based on the results, 158 compounds were identified
in A. muricata, and the human body
was found to absorb 56. It was discovered that 20 compounds were associated
with cholesterol disease. The highest
degree of the disease pathway of target compounds disease was annomuricin, XDH, myocardial ischemia, and metabolic
pathways, respectively. The
PPI showed GAPDH (glyceraldehyde-3-phosphate dehydrogenase) protein also has
the highest degree. BP, CC, MF, and KEEG enrichments that play important roles are the response to drugs, plasma membranes,
protein binding, and metabolic pathways. The molecular docking experiment
confirmed the correlation between ligands and receptors (quercetin-XDH,
coclaurine-ADRB3, fisetin, and robinetin-XDH) with binding energies of –9.3; –8.9; and
–8.8 kcal mol–1, respectively. The
interactions between ligands and receptors are hydrogen, alkyl, Pi-alkyl,
Pi-sigma, and van der Waals bonds. It was discovered that A.
muricata provided therapeutic effects, involving multi-compounds,
multi-targets, multi-diseases, and multi-pathways as well as deep insight into
the pathogenesis of hyperlipidemia. This can be used to design new drugs and
develop novel therapies to treat hyperlipidemia.
Keywords: AMPK signaling; antihyperlipidemia; herbal medicine; phytochemicals; soursop
Abstrak
Durian belanda (Annona muricata L.) adalah salah satu tumbuhan yang mempunyai kesan antihiperlipidemik, tetapi
mekanisme tindakan asasnya masih tidak diketahui. Penyelidikan sebelumnya menggunakan TCMSP, KNApSAcK, ETCM,
SwissTargetPrediction, SuperPred, CTD dan TTD untuk mengenal pasti sasaran
potensi durian belanda sebagai antihiperlipidemik. Oleh itu, kajian ini bertujuan untuk meneroka sebatian aktif durian belanda
dan menunjukkan mekanismenya terhadap hiperlipidemia melalui rangkaian
farmakologi dan dok molekul. OB dan sifat keserupaan
dadah bagi sebatian daripada A. muricata telah disaring berdasarkan parameter Lipinski's Ro5 (Lipinski's Rule of Five). Selepas itu, rangkaian sebatian-sasaran-penyakit-laluan dibina menggunakan
Cytoscape. Rangkaian sasaran PPI (interaksi protein-protein) dibina
menggunakan STRING dan sasaran teras dianalisis menggunakan GO dengan KEGG. Sebatian aktif utama terhadap sasaran telah disahkan oleh analisis dok
molekul. Berdasarkan keputusan, 158 sebatian dikenal pasti dalam A. muricata dan tubuh manusia didapati
menyerap 56. Didapati bahawa 20 sebatian dikaitkan dengan penyakit kolesterol. Peratusan tertinggi laluan penyakit, penyakit sebatian sasaran masing-masing
ialah annomuricin, XDH, iskemia miokardium dan laluan metabolik. PPI menunjukkan protein GAPDH (glyceraldehyde-3-phosphate dehydrogenase)
juga mempunyai peratusan tertinggi. Pengayaan BP, CC, MF
dan KEEG yang memainkan peranan penting ialah tindak balas terhadap ubat,
membran plasma, pengikatan protein dan laluan metabolik. Uji kaji dok molekul mengesahkan korelasi antara ligan dan reseptor
(quercetin-XDH, coclaurine-ADRB3, fisetin, dan robinetin-XDH) dengan tenaga
mengikat masing-masing -9.3; –8.9; dan –8.8 kcal mol–1. Interaksi antara ligan dan reseptor ialah ikatan hidrogen,
alkil, Pi-alkil, Pi-sigma dan van der Waals. Didapati bahawa A. muricata memberikan kesan terapeutik,
melibatkan pelbagai sebatian, pelbagai sasaran, pelbagai penyakit dan pelbagai
laluan serta pandangan mendalam tentang patogenesis hiperlipidemia. Ini boleh digunakan untuk mereka bentuk ubat baharu dan membangunkan terapi
baru untuk merawat hiperlipidemia.
Kata kunci: Antihiperlipidemia; durian belanda; fitokimia; pengisyaratan AMPK; ubat herba
RUJUKAN
Abdul
Wahab, S.M., Jantan, I., Haque, Md.A. & Arshad, L. 2018. Exploring the
leaves of Annona muricata L. as a source of potential anti-inflammatory
and anticancer agents. Frontiers in Pharmacology 9: 661.
Agu,
K.C. & Okolie, P.N. 2017. Proximate composition, phytochemical analysis,
and in vitro antioxidant potentials
of extracts of Annona muricata (Soursop). Food Science &
Nutrition 5(5): 1029-1036.
Berghoff,
S.A., Spieth, L. & Saher, G. 2022. Local cholesterol metabolism
orchestrates remyelination. Trends in Neurosciences 45(4): 272-283.
Cárdenas,
C., Torres-Vargas, J.A., Cárdenas-Valdivia, A., Jurado, N., Quesada, A.R.,
García-Caballero, M., Martínez-Poveda, B. & Medina, M.Á. 2021. Non-targeted
metabolomics characterization of Annona muricata leaf extracts with
anti-angiogenic activity. Biomedicine & Pharmacotherapy 144: 112263.
Chang,
Y.C., Lee, T.S. & Chiang, A.N. 2012. Quercetin enhances ABCA1 expression
and cholesterol efflux through a p38-dependent pathway in macrophages. Journal
of Lipid Research 53(9): 1840-1850.
Coria-Téllez,
A.V., Montalvo-Gónzalez, E., Yahia, E.M. & Obledo-Vázquez, E.N. 2018. Annona
muricata: A comprehensive review on its traditional medicinal uses,
phytochemicals, pharmacological activities, mechanisms of action and toxicity. Arabian
Journal of Chemistry 11(5): 662-691.
Daghestani,
M., Daghestani, M., Daghistani, M., Eldali, A., Hassan, Z.K., Elamin, M.H.
& Warsy, A. 2018. ADRB3 polymorphism rs4994 (Trp64Arg) associates
significantly with bodyweight elevation and dyslipidaemias in Saudis but not
rs1801253 (Arg389Gly) polymorphism in ARDB1. Lipids in Health and Disease 17(1): 58.
Davis,
A.P., Grondin, C.J., Johnson, R.J., Sciaky, D., McMorran, R., Wiegers, J.,
Wiegers, T.C. & Mattingly, C.J. 2019. The comparative toxicogenomics database:
Update 2019. Nucleic Acids Research 47(D1): D948-D954.
Fan,
L., Feng, S., Wang, T., Ding, X., An, X., Wang, Z., Zhou, K., Wang, M., Zhai,
X. & Li, Y. 2022. Chemical composition and therapeutic mechanism of Xuanbai
Chengqi Decoction in the treatment of COVID-19 by network pharmacology,
molecular docking and molecular dynamic analysis. Molecular Diversity 27(1): 81-102.
Gavamukulya,
Y., Abou-Elella, F., Wamunyokoli, F. & AEl-Shemy, H. 2014. Phytochemical
screening, anti-oxidant activity and in
vitro anticancer potential of ethanolic and water leaves extracts of Annona
muricata (Graviola). Asian Pacific Journal of Tropical Medicine 7:
S355-S363.
Gfeller,
D., Grosdidier, A., Wirth, M., Daina, A., Michielin, O. & Zoete, V. 2014.
SwissTargetPrediction: A web server for target prediction of bioactive small
molecules. Nucleic Acids Research 42(W1): W32-W38.
Ghaleb,
Y., Elbitar, S., Philippi, A., El Khoury, P., Azar, Y., Andrianirina, M.,
Loste, A., Abou-Khalil, Y., Nicolas, G., Le Borgne, M., Moulin, P., Di-Filippo,
M., Charrière, S., Farnier, M., Yelnick, C., Carreau, V., Ferrières, J.,
Lecerf, J.M., Derksen, A., Bernard, G., Gauthier, M.S., Coulombe, B.,
Lütjohann, D., Fin, B., Boland, A., Olaso, R., Deleuze, J.F., Rabès, J.P.,
Boileau, C., Abifadel, M. & Varret, M. 2022. Whole exome/genome sequencing
joint analysis of a family with oligogenic familial hypercholesterolemia. Metabolites 12(3): 262.
Gleye,
C., Raynaud, S., Fourneau, C., Laurens, A., Laprévote, O., Serani, L., Fournet,
A. & Hocquemiller, R. 2000. Cohibins C and D, two important metabolites in
the biogenesis of acetogenins from Annona muricata and Annona nutans. Journal of Natural Products 63(9): 1192-1196.
Handayani,
S.I., Sari, M.I.P., Sardjana, M.S., Kusmardi, K., Nurbaya, S., Rosmalena, R.,
Sinaga, E. & Prasasty, V.D. 2022. Ameliorative effects of Annona
muricata leaf ethanol extract on renal morphology of alloxan-induced mice. Applied
Sciences 12(18): 9141.
Ibrahim,
M.A.A., Abdeljawaad, K.A.A., Abdelrahman, A.H.M. & Hegazy, M.E.F. 2021.
Natural-like products as potential SARS-CoV-2 Mpro inhibitors: in-silico drug discovery. Journal of
Biomolecular Structure and Dynamics 39(15): 5722-5734.
Islam,
M.M., Hlushchenko, I. & Pfisterer, S.G. 2022. Low-density lipoprotein
internalization, degradation and receptor recycling along membrane contact
sites. Frontiers in Cell and Developmental Biology 24(10): 826379.
Jebari-Benslaiman,
S., Galicia-García, U., Larrea-Sebal, A., Olaetxea, J.R., Alloza, I.,
Vandenbroeck, K., Benito-Vicente, A. & Martín, C. 2022. Pathophysiology of
atherosclerosis. International Journal of Molecular Sciences 23(6):
3346.
Jiang,
L., Xiong, Y., Tu, Y., Zhang, W., Zhang, Q., Nie, P., Yan, X., Liu, H., Liu, R.
& Xu, G. 2022. Elucidation of the transport mechanism of puerarin and
gastrodin and their interaction on the absorption in a Caco-2 cell monolayer
model. Molecules 27(4): 1230.
Jin,
J., Chen, B., Zhan, X., Zhou, Z., Liu, H. & Dong, Y. 2021. Network
pharmacology and molecular docking study on the mechanism of colorectal cancer
treatment using Xiao-Chai-Hu-Tang. PLoS ONE 16(6): e0252508.
Jing,
Y.S., Ma, Y.F., Pan, F.B., Li, M.S., Zheng, Y.G., Wu, L.F. & Zhang, D.S.
2022. An insight into antihyperlipidemic effects of polysaccharides from
natural resources. Molecules 27(6): 1903.
Ke,
W., Zhou, Y., Lai, Y., Long, S., Fang, L. & Xiao, S. 2022. Porcine
reproductive and respiratory syndrome virus nsp4 positively regulates cellular
cholesterol to inhibit type I interferon production. Redox Biology 49:
102207.
Li,
D., Zhang, J. & Liu, Q. 2022a. Brain cell type-specific cholesterol
metabolism and implications for learning and memory. Trends in Neurosciences 45(5): 401-414.
Li,
J., Zhu, F., Xu, W. & Che, P. 2022b. Therapeutic properties of
isoliquiritigenin with molecular modeling studies: investigation of
anti-pancreatic acinar cell tumor and HMG-CoA reductase inhibitor activity for
treatment of hypercholesterolemia. Archives of Medical Science. https://doi.org/10.5114/aoms/145448
Li,
Y.H., Yu, C.Y., Li, X.X., Zhang, P., Tang, J., Yang, Q., Fu, T., Zhang, X.,
Cui, X., Tu, G., Zhang, Y., Li, S., Yang, F., Sun, Q., Qin, C., Zeng, X., Chen,
Z., Chen, Y.Z. & Zhu, F. 2018. Therapeutic target database update 2018: Enriched
resource for facilitating bench-to-clinic research of targeted therapeutics. Nucleic
Acids Research 46(Database issue): D1121-D1127.
Lin,
H., Guo, X., Liu, J., Liu, P., Mei, G., Li, H., Li, D., Chen, H., Chen, L.,
Zhao, Y., Jiang, C., Yu, Y., Liu, W. & Yao, P. 2022. Improving lipophagy by
restoring Rab7 cycle: Protective effects of quercetin on ethanol-induced liver
steatosis. Nutrients 14(3): 658.
Lipinski,
C.A. 2004. Lead and drug like compounds: The rule of five revolution. Drug
Discovery Today Technologies 1(4): 337-341.
Liu,
C., Fan, F., Zhong, L., Su, J., Zhang, Y. & Tu, Y. 2022. Elucidating the
material basis and potential mechanisms of Ershiwuwei Lvxue Pill acting on
rheumatoid arthritis by UPLC-Q-TOF/MS and network pharmacology. PLoS ONE 17(2): e0262469.
Lu,
S., Tang, L., Zhou, L., Lai, Y., Liu, L. & Duan, Y. 2022. Study on the
multitarget mechanism and active compounds of essential oil from Artemisia
argyi treating pressure injuries based on network pharmacology. Evidence-Based
Complementary and Alternative Medicine 2022: e1019289.
Maharjan,
B., Payne, D.T., Ferrarese, I., Giovanna Lupo, M., Kumar Shrestha, L., Hill,
J.P., Ariga, K., Rossi, I., Sharan Shrestha, S., Panighel, G., Lal (Swagat)
Shrestha, R., Sut, S., Ferri, N. & Dall’Acqua, S. 2022. Evaluation of the
effects of natural isoquinoline alkaloids on low density lipoprotein receptor
(LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) in
hepatocytes, as new potential hypocholesterolemic agents. Bioorganic
Chemistry 121: 105686.
Moghadamtousi,
S.Z., Fadaeinasab, M., Nikzad, S., Mohan, G., Ali, H.M. & Kadir, H.A. 2015. Annona muricata (Annonaceae): A review of its traditional uses, isolated
acetogenins and biological activities. International Journal of Molecular
Sciences 16(7): 15625-15658.
Mollazadeh,
H., Carbone, F., Montecucco, F., Pirro, M. & Sahebkar, A. 2018. Oxidative
burden in familial hypercholesterolemia. Journal of Cellular Physiology 233(8): 5716-5725.
Naik,
A.V. & Sellappan, K. 2020. Chromatographic fingerprint of essential oils in
plant organs of Annona muricata L. (Annonaceae) using HPTLC. Analytical
Chemistry Letters 10(2): 214-226.
Nunes,
V.S., da Silva Ferreira, G. & Quintão, E.C.R. 2022. Cholesterol metabolism
in aging simultaneously altered in liver and nervous system. Aging 14(3): 1549-1561.
Obika,
P., Beamon, J., Ali, S., Kakar, N., Analla, A., Moudden, R.E., Shihadeh, L.,
Patel, S., Hudson, B., Khan, F., Puglisi-Weening, M., Basist, P., Ahmad, S.
& Shahid, M. 2022. 6 - Herbal medicines for the treatment of metabolic
syndrome. In. Herbal Medicines, edited by Sarwat, M. & Siddique, H.
Massachusetts: Academic Press. hlm. 139-191.
Pieme,
C.A., Kumar, S.G., Dongmo, M.S., Moukette, B.M., Boyoum, F.F., Ngogang, J.Y.
& Saxena, A.K. 2014. Antiproliferative activity and induction of apoptosis
by Annona muricata (Annonaceae) extract on human cancer cells. BMC
Complementary and Alternative Medicine 14(1): 516.
Pinto,
Y.O., Festuccia, W.T.L. & Magdalon, J. 2022. The involvement of the
adrenergic nervous system in activating human brown adipose tissue and
browning. Hormones 21(2): 195-208.
Qvit,
N., Joshi, A.U., Cunningham, A.D., Ferreira, J.C.B. & Mochly-Rosen, D.
2016. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein-protein
interaction inhibitor reveals a non-catalytic role for GAPDH oligomerization in
cell death. Journal of Biological Chemistry 291(26): 13608-13621.
Ragasa,
C.Y., Soriano, G., Torres, O.B., Don, M.J. & Shen, C.C. 2012. Acetogenins
from Annona muricata. Pharmacognosy Journal 4(32): 32-37.
Rojas-Armas,
J.P., Arroyo-Acevedo, J.L., Palomino-Pacheco, M., Ortiz-Sánchez, J.M., Calva,
J., Justil-Guerrero, H.J., Castro-Luna, A., Ramos-Cevallos, N., Cieza-Macedo,
E.C. & Herrera-Calderon, O. 2022. Phytochemical constituents and
ameliorative effect of the essential oil from Annona muricata L. leaves
in a murine model of breast cancer. Molecules 27(6): 1818.
Ru,
J., Li, P., Wang, J., Zhou, W., Li, B., Huang, C., Li, P., Guo, Z., Tao, W.,
Yang, Y., Xu, X., Li, Y., Wang, Y. & Yang, L. 2014. TCMSP: A database of
systems pharmacology for drug discovery from herbal medicines. Journal of
Cheminformatics 6(1): 13.
Saito,
R., Smoot, M.E., Ono, K., Ruscheinski, J., Wang, P.L., Lotia, S., Pico, A.R.,
Bader, G.D. & Ideker, T. 2012. A travel guide to Cytoscape plugins. Nature
Methods 9(11): 1069-1076.
Sari,
R.K., Prayogo, Y.H., Sari, R.A.L., Asidah, N., Rafi, M., Wientarsih, I. &
Darmawan, W. 2021. Intsia bijuga heartwood extract and its phytosome as
tyrosinase inhibitor, antioxidant, and sun protector. Forests 12(12):
1792.
Severino,
P., D’Amato, A., Pucci, M., Infusino, F., Adamo, F., Birtolo, L.I., Netti, L.,
Montefusco, G., Chimenti, C., Lavalle, C., Maestrini, V., Mancone, M., Chilian,
W.M. & Fedele, F. 2020. Ischemic heart disease pathophysiology paradigms
overview: From plaque activation to microvascular dysfunction. International
Journal of Molecular Sciences 21(21): 8118.
Sherman,
B.T., Hao, M., Qiu, J., Jiao, X., Baseler, M.W., Lane, H.C., Imamichi, T. &
Chang, W. 2022. DAVID: A web server for functional enrichment analysis and
functional annotation of gene lists (2021 update). Nucleic Acids
Research 50(W1): W216-W221.
Szklarczyk,
D., Gable, A., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., Simonovic, M.,
Doncheva, N., Morris, J., Bork, P., Jensen, L. & von Mering, C. 2018.
STRING v11: protein-protein association networks with increased coverage,
supporting functional discovery in genome-wide experimental datasets. Nucleic
Acids Research 47(D1): D607-D613.
Tripathi,
S., Srivastava, S. & Tripathi, Y.B. 2018. Obesity and its complications: Role
of autophagy. International Journal of Pharmaceutical Sciences and Research 9(8): 3100-3113.
Umar,
A.H., Ratnadewi, D., Rafi, M., Sulistyaningsih, Y.C., Hamim, H. & Kusuma,
W.A. 2022. Drug candidates and potential targets of Curculigo spp.
compounds for treating diabetes mellitus based on network pharmacology,
molecular docking and molecular dynamics simulation. Journal of Biomolecular
Structure and Dynamics. doi: 10.1080/07391102.2022.2135597
van
der Vaart, J.I., Boon, M.R. & Houtkooper, R.H. 2021. The role of AMPK
signaling in brown adipose tissue activation. Cells 10(5): 1122.
Varghese,
J.F., Patel, R., Singh, M. & Yadav, U.C.S. 2021. Fisetin prevents oxidized
low-density lipoprotein–induced macrophage foam cell formation. Journal of
Cardiovascular Pharmacology 78(5): e729-e737.
Wang,
B., Wang, H., Li, Y. & Song, L. 2022a. Lipid metabolism within the bone
micro-environment is closely associated with bone metabolism in physiological
and pathophysiological stages. Lipids in Health and Disease 21(1): 5.
Wang,
H., Wang, H., Zhang, J., Luo, J., Peng, C., Tong, X. & Chen, X. 2022b.
Molecular mechanism of Crataegi Folium and Alisma Rhizoma in the treatment of
dyslipidemia based on network pharmacology and molecular docking. Evidence-Based
Complementary and Alternative Medicine 2022: e4891370.
Wang,
F.X., Zhu, N., Zhou, F. & Lin, D.X. 2021a. Natural aporphine alkaloids with
potential to impact metabolic syndrome. Molecules 26(20): 6117.
Wang,
Q., Du, L., Hong, J., Chen, Z., Liu, H., Li, S., Xiao, X. & Yan, S. 2021b.
Molecular mechanism underlying the hypolipidemic effect of Shanmei Capsule
based on network pharmacology and molecular docking. Technology and Health
Care 29(S1): 239-256.
Xu,
X.Y., Choi, H.S., Park, S.Y., Kim, J.K., Seo, K.H., Kim, H. & Kim, Y.J.
2022. Hibiscus syriacus L. cultivated in callus culture exerts
cytotoxicity in colorectal cancer via Notch signaling-mediated cholesterol
biosynthesis suppression. Phytomedicine 95: 153870.
Yang,
J., Zhang, Y., Jiang, L., Li, C., Sun, Z., Zhang, Y., Lin, T., Jiang, Y. &
Liu, B. 2022. A triple combination strategy of UHPLC-MSn, hypolipidemic
activity and transcriptome sequencing to unveil the hypolipidemic mechanism of Nelumbo
nucifera alkaloids. Journal of Ethnopharmacology 282: 114608.
Yao,
Y.S., Li, T.D. & Zeng, Z.H. 2020. Mechanisms underlying direct actions of
hyperlipidemia on myocardium: An updated review. Lipids in Health and
Disease 19(1): 23.
Ye,
J., Li, L. & Hu, Z. 2021. Exploring the molecular mechanism of action of
Yinchen Wuling powder for the treatment of hyperlipidemia, using network
pharmacology, molecular docking, and molecular dynamics simulation. BioMed
Research International 2021: e9965906.
Yu,
J., Yuan, H., Bao, L. & Si, L. 2021. Interaction between piperine and genes
associated with sciatica and its mechanism based on molecular docking
technology and network pharmacology. Molecular Diversity 25(1): 233-248.
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