Evaluation of the Anticancer Potentials of some Quercetin Derivatives - An in Silico Approach
Keywords:
Quercetin, cancer, molecular docking, in silicoAbstract
Background: Quercetin has been reported to possess anticancer activities. This study was aimed at designing some derivatives of quercetin and evaluating their binding affinities to target proteins implicated in cancer.
Methodology: Derivatives of quercetin were designed with ChemDraw. The targets: Phosphodiesterases (PDEs; 1XMU), Cyclooxygenase-1 (COX-1; 4O1Z); Cyclooxygenase-2 (COX-2; 4M11); Epidermal growth factor receptor (EGFR, 6DUK); α-glucosidase (5KZW); and TNF-α-inducing protein (TNFA, 3VNC) were downloaded from the Protein data bank. Ligands and targets were converted to pdbqt format using PyRx. Carboplatin, carmustine, dacarbazine, dexamethasone, doxorubicin, floxuridine, hydroxyurea, imatinib, lomustine, methotrexate, prednisone, valrubicin and vincristine were used as reference drugs. Molecular docking of the ligands with each of the target proteins was done using Autodock Vina. Discovery Studio was used to visualise ligand-protein binding interactions. Calculated molecular and pharmacokinetic properties were obtained from molinspiration and pKCM websites, respectively.
Results: Ligand 1 (quercetin) had a binding energy of -9.5 kcal/mol. While ligands 10, 39, 34 and 38 had binding energy of -9.6. -9.7, -9.8 and -9.9 kcal/mol, respectively, on PDE. On COX-1 ligand 1 (Quercetin) had a binding energy of -9.8 kcal/mol while ligands 17 and 26 had better binding energy of -10.0 and -10.2 kcal/mol, respectively. On COX-2, the binding energy for ligands 1 (quercetin), 15 and 25 were -10.0, -10.4 and -10.5 kcal/mol, respectively. While binding energy for ligand 1 (quercetin) on EGFR was -8.8 kcal/mol those for ligands 3, 15 and 27 were -9.4 kcal/mol; ligands 37 and 39 were -9.7 kcal/mol. None of the ligands in this study had a better binding energy than quercetin (-7.4 kcal/mol) on TNF. Imatinib and valrubicin had a good binding affinity to all the protein targets.
Conclusion: Some of the derivatives of quercetin (ligands) exhibited better binding affinities to the various cancer target proteins studied in this work. These derivatives have good anticancer potential.
References
American Cancer Society. Cancer Facts and Figures 2021. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf (accessed March 14, 2023)
National Cancer Institute. Cancer Statistics. https://www.cancer.gov/about-cancer/understanding/statistics (accessed March 14, 2023)
World Health Organization. Cancer. https://www.who.int/health-topics/cancer#tab=tab_1 (accessed March 14, 2023).
Stratton MR, Campbell PJ, Futreal PA (2009). The cancer genome. Nature. 458(7239):719-724.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation (2011). Cell. 144(5):646-674.
Vogelstein B, Papadopoulos N, Velculescu VE, et al. (2013). Cancer genome landscapes. Science. ;339(6127):1546-1558.
Weinberg RA. (2013). The biology of cancer. New York: Garland Science.
Kreso A, Dick JE. Evolution of cancer stems cell model (2014). Cell Stem Cell. 14(3):275-291
Siegel RL, Miller KD, Jemal A. (2022). Cancer statistics. CA Cancer J Clin. ;72(1):7-33.
Faivre S, Raymond E, Woynarowski JM, et al. (1996). DNA strand breaks and apoptosis are induced by oxaliplatin in cancer cells. Biochem Pharmacol. 52(6): 1105-1115.
Chabner BA, Roberts TG Jr. (2005). Chemotherapy and the war on cancer. Nat Rev Cancer.;5(1):65-72.
Tariq S, Farooq WA, Siddique YH, et al. (2021). Role of natural products in the discovery of new anti-cancer agents: A review. Anti-Cancer Agents Med Chem. 21(1):1-23.
Yao X, Wang J, Ouyang H, et al.(2016). Quercetin, inflammation and immunity. Nutrients. 8(3):167.
Tang Y, Li X, Liu Z, et al.(2021). Anticancer effects of quercetin in various cancers. Oxid Med Cell Longev. ;2021:1-23.
Kim D, Nguyen TTT, Jo YH, et al. (2020). Quercetin and its derivatives: Syntheses, pharmacological uses, and strategies for improving their efficacy. J Med Chem. 63(3):1052-1071.
Olorunfemi A. Eseyin, Ekarika C. Johnson, Emmanuel I. Etim, Arnold C. Igboasoiyi, Emmanuel Attih, Sunday S. Udobre, Aniekan S. Ebong, Paschal C. Anthony, Edet E. Asanga, Goodnews E. Charles and Akaninyene O. Daniel (2022). In silico evaluation of the antidiabetic potentials of some quercetin derivatives. Journal of Drug Discovery and Research 1(1): 1-15.
Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC (2014). Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 13(4):290-314.).
Netherton SJ, Maurer ME, Zhu G, et al. (2009). Phosphodiesterase 6A knockout promotes angiogenesis in a model of oxygen-induced retinopathy. Am J Pathol. ;174(2):757-768.
Almeida EA, Ilic D, Han Q, Hauck CR, Jin F, Kawakatsu H, Schlaepfer DD, Damsky CH (.2000). Matrix survival sign kcal/mol aling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J Cell Biol. 149(3):741-754.).
Wang D, Dubois RN (2010). Eicosanoids and cancer. Nat Rev Cancer. 10(3):181-193.
Kundu N, Ma X, Holt D, et al. (2009). Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function. Breast Cancer Res Treat. 117(2):235-242.
Dannenberg AJ, Subbaramaiah K. (2003). Targeting cyclooxygenase-2 in human neoplasia: rationale and promise./ Cancer Cell. 4(6):431-436.
Williams CS, Mann M, DuBois RN. (1999). The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 18(55):7908-7916.
Solomon SD, McMurray JJ, Pfeffer MA, et al. (2005). Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. ;352(11):1071-1080.
Sonoshita M, Takaku K, Sasaki N, et al. (2001). Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc (Delta 716) knockout mice. Nat Med. 7(9):1048-1051.
Park SY, Jeong KJ, Lee J, et al. (2012). HOXB9 mediates transcriptional regulation of steroidogenesis-associated factors in prostate cancer cells. PLoS One. 7(8):e42285.
Pao W, Miller VA, Politi KA, et al. (2005). Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. ;2(3):e73.
Sequist LV, Waltman BA, Dias-Santagata D, et al. (2011). Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 3(75):75ra26.
O’Kane GM, Leighl NB (2012). Targeting the EGFR pathway for cancer therapy. Curr Med Chem. 19(21):3168-3177.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Journal of Drug Discovery and Research
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
