Integrating Network Pharmacology and Molecular Docking to investigate Boerhavia diffusa for Pancreatic Cancer Treatment

Year : 2024 | Volume : | : | Page : –
By

Gouri Anil,

Abstract

Objective: In this study, network pharmacology was applied to determine the therapeutic effects of the
bioactive compounds of Boerhavia difusa. Network pharmacology can unearth the underlying
mechanisms between drugs and the disease targets and aids in the discovery of novel medications for
complex conditions such as cancer. Methods: To predict the molecular mechanisms of action of
Boerhavia difusa in the treatment of was screened using the GeneCards database. The Venn diagram
was used to identify the intersecting targets of Boerhavia difusa and Alzheimer’s disease. The obtained
target information was entered into the STRING database to construct a protein-protein interaction
network. DAVID database was used to perform the GO and KEGG pathway enrichment analysis.
Cytoscape software was used to construct the networks, and they key targets were identified. The
binding affinity of the bioactive compounds of Boerhavia difusa with the target proteins was analysed.
PyRx, an online tool was used to perform molecular docking. It was performed using protein structures
from Protein Data Bank (PDB) Database and PubChem. BIOVIA discovery studio software was used
to analyze the protein structure. Result: Upon performing molecular docking, the proteins AKT1,
EGFR, and STAT3 have the best binding affinities with the bioactive compounds of Boerhavia difusa.
Conclusion: According to the results, the phytocompounds have potential therapeutic effects which
provides insight for theoretical basis for the investigation of the pharmacological mechanism of
Boerhavia difusa. Alzheimer’s disease using network pharmacology, the phytocompounds were
obtained from the IMPPAT database. Target information for the phytocompounds and Alzheimer’s
disease.

Keywords: Pancreatic cancer, Boerhavia diffusa, AKT1, EGFR, STAT3, Network Pharmacology, Molecular Docking

How to cite this article: Gouri Anil. Integrating Network Pharmacology and Molecular Docking to investigate Boerhavia diffusa for Pancreatic Cancer Treatment. International Journal of Molecular Biotechnological Research. 2024; ():-.
How to cite this URL: Gouri Anil. Integrating Network Pharmacology and Molecular Docking to investigate Boerhavia diffusa for Pancreatic Cancer Treatment. International Journal of Molecular Biotechnological Research. 2024; ():-. Available from: https://journals.stmjournals.com/ijmbr/article=2024/view=162182

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics. CA Cancer J Clin. 2002;55(2):74–108. doi: 10.3322/canjclin.55.2.74
  2. Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Medicine. 2010;7(4):e1000267 doi:10.1371/journal.pmed.1000267
  3. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388(10039):73–85. doi:10.1016/s0140-6736(16)00141-0
  4. He J, Page AJ, Weiss M, et al. Management of borderline and locally advanced pancreatic cancer: where do we stand? World J Gastroenterol. 2014;20(9):2255–2266. doi:10.3748/wjg.v20.i9.2255
  5. Seufferlein T, Hammel P, Delpero JR, et al. Optimizing the management of locally advanced pancreatic cancer with a focus on induction chemotherapy: expert opinion based on a review of current evidence. Cancer Treat Rev. 2019;77:1–10. doi:10.1016/j.ctrv.2019.05.007
  6. Loehrer PJSr, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an eastern cooperative oncology group trial. J Clin Oncol. 2011;29(31):4105–4112. doi:10.1200/jco.2011.34.8904
  7. Zhen DB, Coveler A, Zanon S, Reni M, Chiorean EG. Biomarker-driven and molecularly targeted therapies for pancreatic adenocarcinoma. Semin Oncol. 2018;45(3):107–115. doi:10.1053/j.seminoncol.2018.05.004
  8. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388(10039):73–85. doi:10.1016/s0140-6736(16)00141-0
  9. Sherman MH, Beatty GL. Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance. Annu Rev Pathol. 2023 Jan 24;18:123-148. doi: 10.1146/annurev-pathmechdis-031621-024600. Epub 2022 Sep 21. PMID: 36130070; PMCID: PMC9877114.
  10. Beatty GL, Werba G, Lyssiotis CA, Simeone DM. 2021. The biological underpinnings of therapeutic resistance in pancreatic cancer. Genes Dev. 35:940–62
  11. Siegel RL, Miller KD, Fuchs HE, Jemal A. 2022. Cancer statistics, 2022. CA Cancer J. Clin. 72:7–33
  12.  Conklin, K.A. (2004) Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness. Integrative Cancer Therapies, 3, 294-300. http://dx.doi.org/10.1177/1534735404270335
  13. Jaiswal, Yogini S., and Leonard L. Williams. “A glimpse of Ayurveda–The forgotten history and principles of Indian traditional medicine.” Journal of traditional and complementary medicine 7.1 (2017): 50-53.
  14. Dutta, Rinku, Roukiah Khalil, Ryan Green, Shyam S. Mohapatra, and Subhra Mohapatra. “Withania somnifera (Ashwagandha) and withaferin A: Potential in integrative oncology.” International journal of molecular sciences 20, no. 21 (2019): 5310.
  15. Shimizu, Tomohiro, María P. Torres, Subhankar Chakraborty, Joshua J. Souchek, Satyanarayana Rachagani, Sukhwinder Kaur, Muzafar Macha, Apar K. Ganti, Ralph J. Hauke, and Surinder K. Batra. “Holy Basil leaf extract decreases tumorigenicity and metastasis of aggressive human pancreatic cancer cells in vitro and in vivo: potential role in therapy.” Cancer letters 336, no. 2 (2013): 270-280.
  16. Akimoto, Miho, Mari Iizuka, Rie Kanematsu, Masato Yoshida, and Keizo Takenaga. “Anticancer effect of ginger extract against pancreatic cancer cells mainly through reactive oxygen species-mediated autotic cell death.” PloS one 10, no. 5 (2015): e0126605.
  17. Rao, Shaival Kamalaksha, Priya Shaival Rao, and B. Nageshwara Rao. “Preliminary investigation of the radiosensitizing activity of guduchi (Tinospora cordifolia) in tumor‐bearing mice.” Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives 22, no. 11 (2008): 1482-1489.
  18. Poornima, P., and T. Efferth. “Ayurveda for cancer treatment.” Med Aromat Plants (Los Angel) 5 (2016): e178.
  19. Govindarajan, M. Vijayakumar, and P. Pushpangadan, “Antioxidant approach to disease management and the role of ‘Rasayana’ herbs of Ayurveda,” Journal of Ethnopharmacology, vol. 99, no. 2, pp. 165–178, 2005
  20. Bairwa, A. Srivastava, and S. M. Jachak, “Quantitative analysis of Boeravinones in the roots of Boerhaavia diffusa by UPLC/PDA,” Phytochemical Analysis, 2014.
  21. Srivastava, D. Saluja, and M. Chopra, “Isolation and screening of anticancer metabolites from Boerhavia diffusa,” Indian Journal of Medical Research, vol. 151, supplement 1, p. S19, 2005.
  22. A. Mungantiwar, A. M. Nair, K. K. Kamal, and M. N. Saraf, “Adaptogenic activity of aqueous extract of the roots of Boerhaavia diffusa linn,” Indian Drugs, vol. 34, no. 4, pp. 184–189, 1997.
  23. Karole, Sarita, Sarika Shrivastava, Shefali Thomas, Bhawana Soni, Shifa Khan, Julekha Dubey, Shashi P. Dubey, Nushrat Khan, and Deepak Kumar Jain. “Polyherbal formulation concept for synergic action: a review.” Journal of Drug Delivery and Therapeutics 9, no. 1-s (2019): 453-466.
  24. Hopkins A.L. Network pharmacology. Nat. Biotechnol. 2007;25:1110–1111.
  25. Zhang B., Wang X., Li S. An integrative platform of TCM network pharmacology and its application on a herbal formula, Qing-Luo-Yin. Evid. Based Complement Alternat. Med. 2013:2013.
  26. Berger S.I., Iyengar R. Network analyses in systems pharmacology. Bioinformatics. 2009;25:2466–2472.
  27. Kibble M., Saarinen N., Tang J., Wennerberg K., Mäkelä S., Aittokallio T. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Nat. Prod. Rep. 2015;32:1249–1266
  28. Liu X., Zhou H. Application of Proteomics Technique in Study of Network Pharmacology. Prog. Pharm. Sci. 2014;38:89–96.
  29. Mohanraj, Karthikeyan, Bagavathy Shanmugam Karthikeyan, R. P. Vivek-Ananth, R. P. Bharath Chand, S. R. Aparna, Pattulingam Mangalapandi, and Areejit Samal. 2018. “IMPPAT: A Curated Database of Indian Medicinal Plants, Phytochemistry and Therapeutics.” Scientific Reports 8 (1): 4329. https://doi.org/10.1038/s41598018-22631-z.
  30. Barton HA, Pastoor TP, Baetcke K, Chambers JE, Diliberto J, Doerrer NG, Driver JH, Hastings CE, Iyengar S, Krieger R, Stahl B, Timchalk C. The acquisition and application of absorption, distribution, metabolism, and excretion (ADME) data in agricultural chemical safety assessments. Crit Rev Toxicol. 2006 Jan;36(1):9-35. doi: 10.1080/10408440500534362. PMID: 16708693
  31. Daina, O. Michielin, V. Zoete. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017; 7:42717. doi: 10.1038/srep42717.
  32. Xiong G, Wu Z, Yi J, Fu L, Yang Z, Hsieh C, Yin M, Zeng X, Wu C, Lu A, Chen X, Hou T, Cao D. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res. 2021 Jul 2;49(W1):W5-W14. doi: 10.1093/nar/gkab255. PMID: 33893803; PMCID: PMC8262709.
  33. Gfeller D, Grosdidier A, Wirth M, Daina A, Michielin O, Zoete V. SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Res. 2014 Jul;42(Web Server issue):W32-8. doi: 10.1093/nar/gku293. Epub 2014 May 3. PMID: 24792161; PMCID: PMC4086140.
  34. Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry. Nat Biotech 25 (2), 197-206 (2007).
  35. Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Stein TI, Nudel R, Lieder I, Mazor Y, Kaplan S, Dahary D, Warshawsky D, Guan-Golan Y, Kohn A, Rappaport N, Safran M, Lancet D. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr Protoc Bioinformatics. 2016 Jun 20;54:1.30.1-1.30.33. doi: 10.1002/cpbi.5. PMID: 27322403
  36. Oliveros, J.C. (2007-2015) Venny. An interactive tool for comparing lists with Venn’s diagrams. https://bioinfogp.cnb.csic.es/tools/venny/index.html
  37. Dennis, G., Sherman, B.T., Hosack, D.A. et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4, R60 (2003). https://doi.org/10.1186/gb-2003-4-9-r60
  38. Tang D, Chen M, Huang X, Zhang G, Zeng L, Zhang G, Wu S, Wang Y. SRplot: A free online platform for data visualization and graphing. PLoS One. 2023 Nov 9;18(11):e0294236. doi: 10.1371/journal.pone.0294236. PMID: 37943830.
  39. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003 Nov;13(11):2498-504. doi: 10.1101/gr.1239303. PMID: 14597658; PMCID: PMC403769.
  40. Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY. cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014;8 Suppl 4(Suppl 4):S11. doi: 10.1186/1752-0509-8-S4-S11. Epub 2014 Dec 8. PMID: 25521941; PMCID: PMC4290687.
  41. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, Mering CV. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613. doi: 10.1093/nar/gky1131. PMID: 30476243; PMCID: PMC6323986.
  42. RCSB Protein Data Bank: A Resource for Chemical, Biochemical, and Structural Explorations of Large and Small Biomolecules. Christine Zardecki, Shuchismita Dutta, David S. Goodsell, Maria Voigt, and Stephen K. Burley
  43. BIOVIA, Dassault Systèmes, Discovery Studio Visualizer,Version 21.1.0, San Diego: Dassault Systèmes, 2021.
  44. UCSF Chimera–a visualization system for exploratory research and analysis. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. J Comput Chem. 2004 Oct;25(13):1605-12.
  45. Laskowski RA, Jabłońska J, Pravda L, Vařeková RS, Thornton JM. PDBsum: Structural summaries of PDB entries. Protein Sci. 2018 Jan;27(1):129-134. doi: 10.1002/pro.3289. Epub 2017 Oct 27. PMID: 28875543; PMCID: PMC5734310.
  46. Small-Molecule Library Screening by Docking with PyRx. Dallakyan S, Olson AJ. Methods Mol Biol. 2015;1263:243-50. The full-text is available at https://www.researchgate.net/publication/273954875_Small-Molecule_Library_Screening_by_Docking_with_PyRx
  47. The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC.
  48. Jendele L, Krivak R, Skoda P, Novotny M, Hoksza D. PrankWeb: a web server for ligand binding site prediction and visualization. Nucleic Acids Res. 2019 Jul 2;47(W1):W345-W349. doi: 10.1093/nar/gkz424. PMID: 31114880; PMCID: PMC6602436.
  49. Manu KA, Kuttan G. Punarnavine induces apoptosis in B16F-10 melanoma cells by inhibiting NF-kappaB signaling. Asian Pac J Cancer Prev. 2009;10(6):1031-7. PMID: 20192578.
  50. Nordin N, Majid NA, Hashim NM, Rahman MA, Hassan Z, Ali HM. Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression. Drug Des Devel Ther. 2015 Mar 10;9:1437-48. doi: 10.2147/DDDT.S77727. PMID: 25792804; PMCID: PMC4362660.
  51. Kaleem, S., Siddiqui, S., Siddiqui, H.H., Badruddeen,  ., Hussain, A., Arshad, M., Akhtar, J. and Rizvi, A. (2016), Eupalitin induces apoptosis in prostate carcinoma cells through ROS generation and increase of caspase-3 activity. Cell Biol Int, 40: 196-203. https://doi.org/10.1002/cbin.10552
  52. Schlessinger J (2014) Receptor tyrosine kinases: legacy of the first two decades. Cold Spring Harb perspect Biol 6, a008912.
  53. Yarden Y and Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12, 553–563
  54. Sarkar FH, Banerjee S, Li Y. Pancreatic cancer: pathogenesis, prevention and treatment. Toxicol Appl Pharmacol. 2007 Nov 1;224(3):326-36. doi: 10.1016/j.taap.2006.11.007. Epub 2006 Nov 11. PMID: 17174370; PMCID: PMC2094388.
  55. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358: 1160–1174.
  56. Knudsen ES, O’Reilly EM, Brody JR, Witkiewicz AK. Genetic diversity of pancreatic ductal adenocarcinoma and opportunities for precision medicine. Gastroenterology. 2016;150(1):48–63. doi: 10.1053/j.gastro.2015.08.056.
  57. Kanda M, Matthaei H, Wu J. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. 2012:730–3. 10.1053/j.gastro.2011.12.042
  58. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission Possible? Nat Rev Drug Discov. 2014; 24:1–24. doi: 10.1038/nrd4389.
  59. Qian ZR, Rubinson DA, Nowak JA, et al. Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. JAMA Oncol. 2018;4(3):1–6. doi: 10.1001/jamaoncol.2017.3420.
  60. Bellacosa A, Kuman CC, DiCristofano A and Testa JR. (2005). Adv. Cancer Res., 94, 29–86.
  61. Luo J, Manning BD and Cantley LC. (2003). Cancer Cell, 4, 257–262.
  62. BjornstiMA and Houghton PJ. (2004). Cancer Cell, 5, 519–523.
  63. Pommier Y, Sordet O, Antony S, Hayward RL and Kohn KW. (2004). Oncogene, 23, 2934–2949
  64. Mayo LD and Donner DB. (2002). Trends Biochem. Sci.,, 27, 462–467
  65. Zhou BP and Hung MC. (2002). Semin. Oncol., 29, 62–70.
  66. Fang X, Hong Y, Dai L, Qian Y, Zhu C, Wu B, et al.. CRH promotes human colon cancer cell proliferation via IL-6/JAK2/STAT3 signaling pathway and VEGF-induced tumor angiogenesis. Mol Carcinogene (2017) 56(11):2434–45. doi: 10.1002/mc.22691
  67. Zhang X, Lu H, Hong W, Liu L, Wang S, Zhou M, et al.. Tyrphostin B42 attenuates trichostatin a-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling. Oncol Rep (2018) 39(4):1892–900. doi: 10.3892/or.2018.6241
  68. Liu X, Wang J, Wang H, Yin G, Liu Y, Lei X, et al.. REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A-JAK2/STAT3 positive feedback loop. Cancer Lett (2015) 362(1):45–60. doi: 10.1016/j.canlet.2015.03.014
  69. Hillmer EJ, Zhang H, Li HS, Watowich SS. STAT3 signaling in immunity. Cytokine Growth factor Rev (2016) 31:1–15. doi: 10.1016/j.cytogfr.2016.05.001
  70. Zhong Z, Wen Z, Darnell JE., Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Sci (New York NY) (1994) 264(5155):95–8. doi: 10.1126/science.8140422
  71. Ruff-Jamison S, Zhong Z, Wen Z, Chen K, Darnell JE, Jr., Cohen S. Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver. J Biol Chem (1994) 269(35):21933–5. doi: 10.1016/S0021-9258(17)31735-0
  72. Wang D, Zheng X, Fu B, Nian Z, Qian Y, Sun R, et al.. Hepatectomy promotes recurrence of liver cancer by enhancing IL-11-STAT3 signaling. EBioMedicine (2019) 46:119–32. doi: 10.1016/j.ebiom.2019.07.058
  73. Nguyen-Jackson HT, Li HS, Zhang H, Ohashi E, Watowich SS. G-CSF-activated STAT3 enhances production of the chemokine MIP-2 in bone marrow neutrophils. J leukocyte Biol (2012) 92(6):1215–25. doi: 10.1189/jlb.0312126
  74. Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: Coming of age. Nat Rev Immunol (2018) 18(5):309–24. doi: 10.1038/nri.2017.142
  75. Vara JÁF, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.Return to ref 223 in article
  76. Kim S, Chen J, Cheng T, et al. PubChem 2023 update. Nucleic Acids Res. 2023;51(D1):D1373–D1380. doi:10.1093/nar/gkac956
Ahead of Print Subscription Original Research
Volume
Received April 4, 2024
Accepted May 16, 2024
Published August 8, 2024
Views: 68

Check Our other Platform for Workshops in the field of AI, Biotechnology & Nanotechnology.
Learn more
Check Out Platform for Webinars in the field of AI, Biotech. & Nanotech.
Learn more