Exploring Anti-inflammatory Targets of Flavonoids through Integrated Molecular Docking and Network Pharmacology
DOI:
https://doi.org/10.35516/jjps.v18i1.2713Keywords:
Anti-inflammatory, Ferulic acid, Hesperidin, Molecular docking, Network Pharmacology, Quercetin, RutinAbstract
Inflammation is a complex physiological response associated with numerous diseases. Flavonoids, a class of natural compounds widely distributed in plants, have demonstrated promising anti-inflammatory properties. However, their comprehensive mechanisms of action and potential molecular targets remain indefinable. In the present study, we employed a network pharmacology approach combined with molecular docking to investigate the anti-inflammatory effects of some flavonoids. Initially, we collected and curated a comprehensive database such as ADMET parameters and targets from Swiss ADME, ADMET 2.O and Swiss target predication. We further constructed a protein-protein interaction network to identify key proteins involved in inflammation by using string database. Subsequently, we integrated the flavonoid dataset with the protein network to establish potential flavonoid-protein interactions by using Cytosacpe vina. The GO and KEGG enrichment analysis were done with the help of David database. Molecular docking was accomplished through Autodock Vina, and assessed the binding affinity of selected flavonoids towards the identified target proteins. The docking analysis provided insights into the specific interactions between flavonoids and target proteins, elucidating the potential mechanisms underlying their anti-inflammatory effects. The bioactive components ferulic acid, quercetin, rutin and hesperidin modulates many molecular and cellular processes and then exerts anti-inflammatory effects. From the analysis the key targets were participated in inflammatory bowel disease, IL 17 signaling pathway, TNF signaling pathway, cytokine-mediated signaling pathway, rheumatoid arthritis, lipopolysaccharides etc. Further molecular docking studies also revealed that binding affinity of selected flavonoids were higher than that of diclofenac.
References
Patil K. R., Mahajan U. B., Unger B. S., Goyal S. N., Belemkar S., Surana S. J. Animal models of inflammation for screening of anti-inflammatory drugs: Implications for the discovery and development of phytopharmaceuticals. International Journal of Molecular Sciences. 2019; 20(18): accepted manuscript. DOI: https://doi.org/10.3390/ijms20184367
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770891/
Dewanjee S., Dua T. K., Sahu R. Potential anti-inflammatory effect of Leea macrophylla Roxb. leaves: A wild edible plant. Food and Chemical Toxicology. 2013; 59: 514-520. DOI: https://doi.org/10.1016/j.fct.2013.06.038
Furman D., Campisi J., Verdin E., Carrera-Bastos P., Targ S., Franceschi C. Chronic inflammation in the etiology of disease across the life span. Nature Medicine. 2019; 25(12): 1822-1832. DOI: https://doi.org/10.1038/s41591-019-0675-0
Pahwa R. and Jialal I. Chronic inflammation. NIH.gov. StatPearls Publishing, 2019; Available from: https://www.ncbi.nlm.nih.gov/books/NBK493173/
Debnath S., Ghosh S., Hazra B. Inhibitory effect of Nymphaea pubescens Willd. flower extract on carrageenan-induced inflammation and CCl4-induced hepatotoxicity in rats. Food and Chemical Toxicology. 2013; 59: 485-491. DOI: https://doi.org/10.1016/j.fct.2013.06.036
Ren J., Ren M., Mo Z., Lei M. Study on anti-inflammatory mechanism of Angelica pubescens based on network pharmacology and molecular docking. Sage Journal. 2022; 18(1): 466-469.
Zhu N., Hou J. Molecular mechanism of the anti-inflammatory effects of Sophorae flavescentis Aiton identified by network pharmacology. Scientific Reports. 11(1). Available from: DOI: https://doi.org/10.1038/s41598-020-80297-y
https://www.nature.com/articles/s41598-020-80297-y.pdf?origin=ppub
Arakawa T., Higuchi K., Fukuda T., Fujiwara Y., Kobayashi K., Kuroki T. Prostaglandins in the stomach: an update. Journal of Clinical Gastroenterology.1998; 27: S1–11. DOI: https://doi.org/10.1097/00004836-199800001-00003
Bindu S., Mazumder S., Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochemical Pharmacology. 2020; 114147. DOI: https://doi.org/10.1016/j.bcp.2020.114147
Zhang Q., Li X, Li J., Hu Y., Liu J., Wang F. Mechanism of anti-inflammatory and antibacterial effects of qing xiao wu wei decoction based on network pharmacology, molecular docking and in vitro experiments. Frontiers in Pharmacology. 2021; 12. DOI: https://doi.org/10.3389/fphar.2021.678685
Mahdy A. M., Galley H. F., Abdel-Wahed M. A., el-Korny K. F., Sheta S. A., Webster N. R. Differential modulation of interleukin-6 and interleukin-10 by diclofenac in patients undergoing major surgery. British Journal of Anaesthesia. 2023; 797–802. Available from: https://pubmed.ncbi.nlm.nih.gov/12173196/ DOI: https://doi.org/10.1093/bja/88.6.797
Oguntibeju O. Medicinal plants with anti-inflammatory activities from selected countries and regions of Africa. Journal of Inflammation Research. 2018; 11: 307-317. Available from: DOI: https://doi.org/10.2147/JIR.S167789
http://europepmc.org/articles/PMC6086115
Panche A. N., Diwan A. D., Chandra S. R. Flavonoids: an overview. Journal of Nutritional Science. 2016; 5(e47). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465813/ DOI: https://doi.org/10.1017/jns.2016.41
Pietta P. G. Flavonoids as Antioxidants. Journal of Natural Products. 2000; 63(7): 1035–1042. DOI: https://doi.org/10.1021/np9904509
Kumar S., Pandey A. K. Chemistry and Biological Activities of Flavonoids: An Overview. The Scientific World Journal. 2013; 1–16. DOI: https://doi.org/10.1155/2013/162750
Ginwala R., Bhavsar R., Chigbu D. I., Jain P., Khan Z. K. Potential role of flavonoids in treating chronic inflammatory diseases with a special focus on the anti-inflammatory activity of apigenin. Antioxidants. 2019; 8: 35. DOI: https://doi.org/10.3390/antiox8020035
Zhao S., Liu Z., Wang M., He D., Liu L., Shu Y. Anti-inflammatory effects of Zhishi and Zhiqiao revealed by network pharmacology integrated with molecular mechanism and metabolomics studies. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology. 2018; 50: 61–72. https://pubmed.ncbi.nlm.nih.gov/30466993/ DOI: https://doi.org/10.1016/j.phymed.2018.09.184
Xiang C., Liao Y., Chen Z., Xiao B., Zhao Z., Li A. Network pharmacology and molecular docking to elucidate the potential mechanism of Ligusticum chuanxiong against osteoarthritis. Frontiers in Pharmacology. 2022; 13: 854215. https://pubmed.ncbi.nlm.nih.gov/35496280/ DOI: https://doi.org/10.3389/fphar.2022.854215
Obaidullah A. J., Alanazi M. M., Alsaif N.A., Alanazi A.S., Albassam H. Network pharmacology- and molecular docking-based identification of potential phytocompounds from Argyreia capitiformis in the treatment of inflammation. Garg R, editor. Evidence-Based Complementary and Alternative Medicine. 2022; 1–22. DOI: https://doi.org/10.1155/2022/8037488
Dar A.M. and Mir S. Molecular docking: approaches, types, applications and basic challenges. Journal of Analytical & Bioanalytical Techniques. 2017; 08(02). DOI: https://doi.org/10.4172/2155-9872.1000356
Forli S., Huey R., Pique M.E., Sanner M.F., Goodsell D.S., Olson A. J. Computational protein–ligand docking and virtual drug screening with the AutoDock suite. Nature Protocols. 2016; 11(5): 905-919. DOI: https://doi.org/10.1038/nprot.2016.051
Guan L., Yang H., Cai Y., Sun L., Li P. D. ADMET-score -a comprehensive scoring function for evaluation of chemical drug-likeness. Med Chem Comm. 2019; 10(1): 148-157. DOI: https://doi.org/10.1039/C8MD00472B
Luo W., Deng J., He J., Yin L., You R., Zhang L. Integration of molecular docking, molecular dynamics and network pharmacology to explore the multi-target pharmacology of fenugreek against diabetes. Journal of Cellular and Molecular Medicine. 2023; Available from: https://pubmed.ncbi.nlm.nih.gov/37257051/ DOI: https://doi.org/10.1111/jcmm.17787
Wang K., Wang Y., Yan J., Hou C., Zhong X., Zhao Y. Network pharmacology and molecular docking integrated strategy to the screening of active components and mechanisms of Stephaniae tetrandrae radix on breast cancer. Processess. 2022; 10(11): 2340. Available from: https://www.mdpi.com/2227-9717/10/11/2340 DOI: https://doi.org/10.3390/pr10112340
Gfeller D., Grosdidier A., Wirth M., Daina A., Michielin O., Zoete V. Swiss target prediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Research. 2014; 1: 42: 32-38. DOI: https://doi.org/10.1093/nar/gku293
https://academic.oup.com/nar/article/42/W1/W32/2435215#86861076
Zhang M., Yang J., Zhao X., Zhao Y., Zhu S. Network pharmacology and molecular docking study on the active ingredients of Qidengmingmu capsule for the treatment of diabetic retinopathy. Scientific Reports. 2021; 11(1): 7382. Available from: DOI: https://doi.org/10.1038/s41598-021-86914-8
https://www.nature.com/articles/s41598-021-86914-8
Tong T., Cheng B., Tie S., Zhan G., Ouyang D., Cao J. Exploring the mechanism of Epimedii folium and ginseng radix against vascular dementia based on network pharmacology and molecular docking analysis: pharmacological mechanisms of EH-PN for VD. Medicine. 2022; 101(47): e31969-31969. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9704979 DOI: https://doi.org/10.1097/MD.0000000000031969
Raman K. Construction and analysis of protein–protein interaction networks. Automated Experimentation. 2010; 2(1): 1-2. DOI: https://doi.org/10.1186/1759-4499-2-2
Ren J., Ren M., Mo Z., Lei M. Study on anti-inflammatory mechanism of angelica pubescens based on network pharmacology and molecular docking. Sage journal. 2022; 18(1): 1934578X2211466–6. DOI: https://doi.org/10.1177/1934578X221146616
Wang C., Chen H., Ma S. T., Mao B. B., Chen Y., Xu H. N. A network pharmacology approach for exploring the mechanisms of Panax notoginseng saponins in ischaemic stroke. Evidence-Based Complementary and Alternative Medicine. 2021; 5582782. Available from: https://pubmed.ncbi.nlm.nih.gov/34434246 DOI: https://doi.org/10.1155/2021/5582782
Huang D. W., Sherman B. T., Tan Q., Kir J., Liu D., Bryant D. DAVID bioinformatics resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Research. 2007; 35(suppl 2): W169-175. DOI: https://doi.org/10.1093/nar/gkm415
Nandi A., Das A., Dey Y. N., Roy K. K. The abundant phytocannabinoids in rheumatoid arthritis: therapeutic targets and molecular processes identified using integrated bioinformatics and network pharmacology. Life. 2023; 13(3): 700. DOI: https://doi.org/10.3390/life13030700
Meng X. Y., Zhang H. X., Mezei M., Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Current Computer Aided-Drug Design. 2011; 7(2): 146-157. DOI: https://doi.org/10.2174/157340911795677602
Ferreira L., dos Santos R., Oliva G., Andricopulo A. Molecular docking and structure-based drug design strategies. Molecules. 2015; 20(7): 13384-13421. DOI: https://doi.org/10.3390/molecules200713384
Zhang Q., Li R., Liu J., Peng W., Gao Y., Wu C. In silico screening of anti-inflammatory constituents with good drug-like properties from twigs of Cinnamomum cassia based on molecular docking and network pharmacology. Tropical Journal of Pharmaceutical Research. 2021; 18(10): 2125-2131. DOI: https://doi.org/10.4314/tjpr.v18i10.18
Seeliger D., de Groot B. L. Ligand docking and binding site analysis with PyMOL and Autodock Vina. Journal of Computer-Aided Molecular Design. 2010; 24(5): 417-422. DOI: https://doi.org/10.1007/s10822-010-9352-6
Megha K. B., Joseph X., Akhil V., Mohanan P. V. Cascade of immune mechanism and consequences of inflammatory disorders. Phytomedicine. 2021; 91: 153712. Available from: DOI: https://doi.org/10.1016/j.phymed.2021.153712
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373857
Vane J. R. and Botting R. M. Anti-inflammatory drugs and their mechanism of action. Inflammation Research: Journal of the European Histamine Research Society. 1998; 47(Suppl 2): S78-87. Available from: https://pubmed.ncbi.nlm.nih.gov/9831328 DOI: https://doi.org/10.1007/s000110050284
Barakat, A., Abu-Hameda, Y., Aljamal, S., Al Muhaissen, S., Bisharat, L., Birardi, A., & AlKhatib, H. S. Formulation and evaluation of controlled-release, carrageenan-based powder formulations filled into hard gelatin capsules. Jordan Journal of Pharmaceutical Sciences. 2023; 16(2): 474.
https://doi.org/10.35516/jjps.v16i2.1531 DOI: https://doi.org/10.35516/jjps.v16i2.1531
Maslov, O., Komisarenko, M., Kolisnyk, S., & Derymedvid, L. Evaluation of Anti-Inflammatory, Antioxidant Activities and Molecular Docking Analysis of Rubus idaeus Leaf Extract. Jordan Journal of Pharmaceutical Sciences, 2024; 17(1): 105-122. https://doi.org/10.35516/jjps.v17i1.1808 DOI: https://doi.org/10.35516/jjps.v17i1.1808
Abu-Darwish, D., Shibli, R., & Al-Abdallat, A. M. Phenolic Compounds and Antioxidant Activity of Chiliadenus montanus (Vhal.) Brullo. grown in vitro. Jordan Journal of Pharmaceutical Sciences, 2024; 17(3): 611-628. https://doi.org/10.35516/jjps.v17i3.2248. DOI: https://doi.org/10.35516/jjps.v17i3.2248
Leyva-López N., Gutierrez-Grijalva E., Ambriz-Perez D., Heredia J. Flavonoids as cytokine modulators: a possible therapy for inflammation-related diseases. International Journal of Molecular Sciences. 2016; 17(6): 921. DOI: https://doi.org/10.3390/ijms17060921
Zhang G., Li Q., Chen Q., Su S. Network Pharmacology: A New Approach for Chinese Herbal Medicine Research. Evidence-Based Complementary and Alternative Medicine. 2013; 1-9. DOI: https://doi.org/10.1155/2013/621423
Shannon P. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Research. 2003; 13(11): 2498-2504. Available from: DOI: https://doi.org/10.1101/gr.1239303
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC403769/
Gandhi H., Worch R., Kurgonaite K., Hintersteiner M., Schwille P., Bokel C. Dynamics and interaction of interleukin-4 receptor subunits in living cells. Biophysical Journal. 2014; 107(11): 2515-2527. DOI: https://doi.org/10.1016/j.bpj.2014.07.077
Gaffen S. L. Structure and signalling in the IL-17 receptor family. Nature Reviews Immunology. 2009; 9(8): 556-567. DOI: https://doi.org/10.1038/nri2586
Ge Y., Huang M., Yao Y. Biology of Interleukin-17 and Its Pathophysiological Significance in Sepsis. Frontiers in Immunology. 2020; 11. Available from: DOI: https://doi.org/10.3389/fimmu.2020.01558
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399097
Zenobia C., Hajishengallis G. Basic biology and role of interleukin-17 in immunity and inflammation. Periodontology. 2015; 69(1): 142-159. DOI: https://doi.org/10.1111/prd.12083
Lee S. H., Wonye J. K., Kim S.Y., Jung K., Cho M. L. Interferon-gamma regulates inflammatory cell death by targeting necroptosis in experimental autoimmune arthritis. Scientific Reports. 2017; 7(1): 31. DOI: https://doi.org/10.1038/s41598-017-09767-0
Ortiz L.A., Dutreil M., Fattman C., Pandey A. C., Torres G., Go K. Interleukin 1 receptor antagonist mediates the anti-inflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(26): 11002-11007. https://www.ncbi.nlm.nih.gov/pubmed/17569781 DOI: https://doi.org/10.1073/pnas.0704421104
Shouval D. S., Ouahed J., Biswas A., Goettel J.A., Horwitz B.H., Klein C. Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans. Advances in immunology. 2014; 122: 177-210. Available from: DOI: https://doi.org/10.1016/B978-0-12-800267-4.00005-5
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741283
Carey A. J., Tan C.K., Ulett G. C. Infection-induced IL-10 and JAK-STAT. JAK-STAT. 2012; 1(3): 159-167. DOI: https://doi.org/10.4161/jkst.19918
Schulke S. Induction of interleukin-10 producing dendritic cells as a tool to suppress allergen-specific T helper 2 responses. Frontiers in Immunology. 2018; 9. DOI: https://doi.org/10.3389/fimmu.2018.00455
Lawrence T. The nuclear factor NF-B pathway in inflammation. Cold Spring Harbor Perspectives in Biology. 2009; 1(6): 001651-1661. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882124 DOI: https://doi.org/10.1101/cshperspect.a001651
Zhang T., Ma C., Zhang Z., Zhang H., Hu H. NF‐κB signaling in inflammation and cancer. Med Comm. 2021; 2(4). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8706767 DOI: https://doi.org/10.1002/mco2.104
Rudensky A. Y. Regulatory T cells and FOXP3. Immunological Reviews. 2011; 241(1): 260-268. DOI: https://doi.org/10.1111/j.1600-065X.2011.01018.x
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