Molecular Docking Study on Cholangiocarcinoma Target Protein with Natural Plant Derived Ligands for Potential Therapeutic Applications
Keywords:
Hepatic cancer, Cholangiocarcinoma, Molecular docking, RIPK1, Natural ligands, Phytochemicals, Drug discoveryAbstract
Cholangiocarcinoma (CCA) is an aggressive and malignant form of bile cancer. Its late detection, limited therapeutic options, and low survival chances poses major clinical challenges. Receptor Interacting Protein Kinase 1 (RIPK1) is a mediator of cell death and inflammatory responses in the body. With its ability to promote cancer by creating a cancer microenvironment, RIPK1 has recently gained attention, as a potential target for cancer treatment. Tumor Necrosis Factor (TNF) is what activates the RIPK1, and induces the necroptosis pathway. This study focuses on molecular docking techniques to identify phytochemicals thar are potential inhibitors of RIPK1 and TNF, by comparing their binding affinity. The results reveal that Withanolide, Ginkgolide, and Silymarin demonstrated strongest interaction with RIPK1. Withanolide being the best among these to bind with TNF as well. Drug-likeness, ADME, Rule of five assessments were carried out to study the pharmacokinetic properties of those phytochemicals to further confirm their effects. The findings suggest that these phytochemicals could serve as potential inhibitors of RIPK1, offering a natural and targeted approach for CCA therapy. Nonetheless, additional laboratory and animal studies are needed to confirm their anticancer effects, assess potential toxicity, and better understand how they work. This study shows the importance of integrating computational drug discovery approaches with natural compound research to develop novel and effective therapeutic strategies for cholangiocarcinoma
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Ashburn, T. T., & Thor, K. B. (2004). Drug repositioning: identifying new uses for old drugs. Nature Reviews Drug Discovery, 3(8), 673–681.
Aune, D., et al. (2017). Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality—a systematic review and dose-response meta-analysis of prospective studies. International Journal of Epidemiology, 46(3), 1029–1056.
Banales, J. M., et al. (2019). Molecular pathogenesis of cholangiocarcinoma. New England Journal of Medicine, 381(6), 558–571.
Bohacek, R. S., McMartin, C., & Rich, D. H. (1996). Multiple highly diverse structures complementary to enzyme binding sites from combinatorial libraries. Journal of Medicinal Chemistry, 39(16), 2973–2978.
Bridgewater, J., et al. (2017). Biliary tract cancer: ESMO Clinical Practice Guidelines. Annals of Oncology, 28(suppl_4), iv19-iv31.
Burnstock, G. (2016). Purinergic signaling in the liver. Purinergic Signalling, 12(2), 205–221.
Christgen, H., et al. (2019). RIPK1 and RIPK3 in cancer: A complex relationship. International Journal of Molecular Sciences, 20(15), 3749.
Deng, L., et al. (2015). Patient-specific pathway-based network analysis for personalized medicine. Proceedings of the National Academy of Sciences, 112(4), 1109–1114.
Deng, Y., et al. (2020). RIPK1: A double-edged sword in cancer. Cancers, 12(10), 2826.
Dixon, C., et al. (2017). Human RIPK1 mediates diverse cell death and proinflammatory responses in response to TNFα. Cell Death & Disease, 8(1), e2528.
Ferreira, L. G., et al. (2010). Molecular docking and structure-based drug design strategies. Molecules, 15(7), 4429–4455.
Galluzzi, L., et al. (2016). Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2015. Cell Death & Differentiation, 23(3), 486–521.
Green, D. R. (2011). Apoptotic pathways. Cold Spring Harbor Perspectives in Biology, 3(10), a005239.
Han, J., et al. (2011). Necroptosis: a novel mode of programmed cell death. Pharmacological Reviews, 63(2), 457–481.
Joshi, A., et al. (2021). Global trends in the incidence of cholangiocarcinoma. Liver International, 41(1), 22–30.
Kanehisa, M., & Goto, S. (2000). KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research, 28(1), 27-30.
Karmas, A., et al. (2020). Health benefits of fruits and vegetables. Nutrients, 12(10), 2925.
Khan, N., et al. (2018). Anticancer properties of natural products: An update. Current Pharmaceutical Design, 24(1), 105–119.
Kitchen, D. B., et al. (2004). Docking and scoring in drug design. Drug Discovery Today, 9(12), 525–533.
Klein, H. A., et al. (2020). The changing epidemiology of cholangiocarcinoma. Current Opinion in Gastroenterology, 36(2), 119–126.
Koo, J. B., et al. (2020). RIPK1-mediated necroptosis promotes inflammation and tumor progression in gastric cancer. Cell Death & Disease, 11(1), 1–14.
Lammert, F., & Marschall, H. U. (2022). Cholangiocarcinoma: Epidemiology, risk factors, and the role of the microbiome. Nature Reviews Gastroenterology & Hepatology, 19(10), 652–668.
Li, C. Z., Lin, Y. X., Huang, T. C., Pan, J. Y., & Wang, G. X. (2019). Receptor-Interacting Protein Kinase 1 promotes cholangiocarcinoma proliferation and lymphangiogenesis through the Activation Protein 1 pathway. OncoTargets and Therapy, 12, 9029-9040.
Massarweh, N. N., et al. (2021). Systematic review and meta-analysis of survival outcomes after surgical resection for intrahepatic cholangiocarcinoma. Annals of Surgery, 273(1), 101–110.
Melo, S. A., et al. (2015). Cholangiocarcinoma: Molecular mechanisms and therapeutic targets. World Journal of Gastroenterology, 21(26), 7981–7993.
Minihane, A. M., et al. (2015). Polyphenols and their role in the prevention of diseases related to oxidative stress. Free Radical and Antioxidant Protocols, 169–189.
Misra, S., et al. (2022). Cholangiocarcinoma: A comprehensive review. Cancer Treatment Reviews, 98, 102236.
Mizuno, N., et al. (2021). Global trends in the incidence of cholangiocarcinoma: a systematic review. Journal of Hepato-Biliary-Pancreatic Sciences, 28(5), 379–391.
Moeini, A., et al. (2023). Current and emerging therapies for cholangiocarcinoma. Cancers, 15(2), 527.
Scalbert, A., et al. (2005). Dietary polyphenols and the prevention of diseases. Critical Reviews in Food Science and Nutrition, 45(4), 287–306.
Shindoh, J., et al. (2022). Molecular profiling of cholangiocarcinoma for targeted therapy. Journal of Hepatology, 76(1), 171–182.
Shoichet, B. K. (2004). Virtual screening of chemical libraries. Nature, 432(7019), 862–865.
Sia, D., et al. (2019). Integrated genomic and transcriptomic profiling of cholangiocarcinoma identifies therapeutic vulnerabilities. Gastroenterology, 156(6), 1670–1685.e10.
Thanan, R., et al. (2019). Risk factors and molecular mechanisms of cholangiocarcinoma. Cancer Letters, 450, 116–124.
Verdonk, M. L., et al. (2003). Structure-based design of kinase inhibitors with broad-spectrum activity. Current Topics in Medicinal Chemistry, 3(2), 197–212.
Wojdyło, A., et al. (2021). Recent advances in the study of bioactive compounds from fruits and vegetables: Extraction methods, bioavailability, and health effects. Nutrients, 13(1), 147.
Yang, J., et al. (2020). Cinnamon: A review of its antidiabetic properties and potential mechanisms. Nutrients, 12(9), 2526.
Zhou, Y., et al. (2020). Advances in protein-ligand docking. International Journal of Molecular Sciences, 21(18), 6994
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