• Isnatin Miladiyah Pharmacology Department, Faculty of Medicine, Islamic University of Indonesia, Yogyakarta
  • Jumina Jumina Chemistry Department, Faculty of Mathematics and Natural Sciences, GadjahMada University, Yogyakarta
  • Sofia Mubarika Haryana Histology and Cell Biology Department, Faculty of Medicine, GadjahMada University, Yogyakarta
  • Mustofa Mustofa Pharmacology and Therapeutic Department, Faculty of Medicine, Gadjah Mada University, Yogyakarta



Xanthones, Molecular docking, Anticancer, COX-2, Selectivity


Objective: To demonstrate the potential ofdifferent xanthone derivatives as cyclooxygenase-2 (COX-2) inhibitor agents and their selectivity against cycloooxygenase-1 (COX-1) and COX-2 using molecular simulation.

Methods: Nine novel xanthone derivatives (compounds A-I) were employed to dock against protein COX-2 (Protein Data Bank/PDB ID: 1CX2) and COX-1 (PDB ID: 3N8Z). Celecoxib, a selective COX-2 inhibitor, was chosen as a control compound. The free binding energy produced by the docking was scored using Protein-Ligand Ant System (PLANTS) and the hydrogen bonds (H-bonds) between ligands and enzymes were visualised using Pymol.

Results: Molecular docking studies revealed that celecoxib docked to the active site of COX-2 enzyme, but not to COX-1; whereasxanthone derivatives docked to the active site of both COX-2 and COX-1. Free binding energy of xanthone derivatives ranged between-73,57 to-79,18 and between-73,06 to-79,25 against COX-2 and COX-1, respectively, and-78,13 against celecoxib. H-bonds in the molecule of xanthone derivatives and COX-2 protein were found in amino acid residues Arg120, Tyr355, Tyr385,and Ser353. There was an insignificant difference between the free binding energyof xanthone derivatives against COX-2 and against COX-1, suggesting that their inhibition was non-selective.

Conclusion: In conclusion, in silico studies showed that xanthone derivatives could be effective as potential inhibitors against COX-2, although they are not selective.


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Jarapula R, Gangarapu K, Manda S, Rekulapally S. Seynthesis, in vivo anti-inflammatory activity, and molecular docking studies of new isatin derivatives. Int J Med Chem 2016.

Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, et al. Structural basis for selective inhibition of cyclooxigenase-2 by anti-inflammatory agents. Nature 1996;384:400–2.

Barone M, Pannuzzo G, Santagati A, Catalfo A, Guidi G De, Cardile V. Molecular docking and fluorescence characterization of benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives, a novel class of selective cyclooxygenase-2 Inhibitors. Molecules 2014;19:6106–22.

Moossavi S, Bishehsari F. Inflammation in sporadic colorectal cancer. Arch Iranian Med 2012;15:166–70.

Deng S, Hu B, Shen K, Xu L. Inflammation, macrophage in cancer progression and chinese herbal treatment. J Basic Clin Pharm 2012;3:269–72.

Hanahan D, Weinberg RA. Review hallmarks of cancer: the next generation. Cell 2011;144:646–74.

Rothwell PM, Fowkes FGR, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377:31–41.

Wang WH, Huang JQ. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis. J Nat Cancer Inst 2003;95:1784–91.

McCormack V, Hung RJ, Brenner DR, Bickeboller H, Rosenberger A, Muscat JE, et al. Aspirin and NSAID use and lung cancer risk: a pooled analysis in the international lung cancer consortium (ILCCO). Cancer Causes Control 2011;22:1709–20.

Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE. Aspirin intake and survival after breast cancer. J Clin Oncol 2010;28:1467–72.

Chang ET, Zheng T, Weir EG, Borowitz M, Mann RB, Spiegelman D, et al. Aspirin and the risk of hodgkin’s lymphoma in a population-based case-control study. J Nat Cancer Inst 2004;96:305–15.

Bosetti C, Gallus S, Vecchia C La. Aspirin and cancer risk: a summary review to 2007. Cancer Prevention II Recent Res Cancer Res 2009;181:31–51.

Gu Q, De Wang J, Xia HHX, Lin MCM, He H, Zou B, et al. Activation of the caspase-8/Bid and Bax pathways in aspirin-induced apoptosis in gastric cancer. Carcinogenesis 2005;26:541–6.

Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemostasis 2011;9:237–49.

Chattopadhyay M, Kodela R, Nath N, Barsegian A. Hydrogen sulfide-releasing aspirin suppresses NF-k B signaling in estrogen receptor negative breast cancer cells in vitro and in vivo. Biochem Pharmacol 2012;83:723–32.

Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, Dubois RN. Cyclooxygenases regulates angiogenisis induced by colon cancer cells. Cell 1998;93:705–16.

Hardwick JCH, van Santen M, van den Brink GR, van Deventer SJH, Peppelenbosch MP. DNA array analysis of the effects of aspirin on colon cancer cells: involvement of Rac1. Carcinogenesis 2004;25:1293–8.

Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. JAMA 2000;284:1247–55.

Krishna PS, Vani K, Prasad MR, Samatha B, Bindu NSVSSSLH, Charya MAS, et al. In silico molecular docking analysis of prodigiosin and cycloprodigiosin as COX-2 inhibitors. Springerplus 2013;2:172-7.

Mukesh B, Rakesh K. Molecular docking: a review. Int J Res Ayurveda Pharm 2011;2:1746–51.

Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-basde drug discovery NIH public access. Curr Comput Aided Drug Des 2011;7:146–57.

Lavecchia A, Giovanni CD. Virtual screening strategies in drug discovery: a critical review. Curr Med Chem 2013;20:2839–60.

Chen LG, Yang LL, Wang CC. Anti-inflammatory activity of mangostins from Garcinia mangostana. Food Chem Toxicol 2008;46:688–93.

Crockett SL, Poller B, Tabanca N, Pferschy-Wenzig EM, Kunert O, Wedge DE, et al. Bioactive xanthones from the roots of hypericum perforatum (common St John’s wort). J Sci Food Agric 2011;91:428–34.

Chan KM, Hamzah R, Rahaman AA, Jong VYM, Khong HY, Rajab NF, et al. The pyranoxanthone inophyllin a induces oxidative stress mediated-apoptosis in Jurkat T lymphoblastic leukemia cells. Food Chem Toxicol 2012;50:2916–22.

Yi T, Yi Z, Cho SG, Luo J, Pandey MK, Agarwal BB, et al. Gambogic acid inhibits angiogenesis an dprostate tumor growth by supressing VEGFR2 signaling. Cancer Res 2008;68:1843–50.

Mohan S, Ibrahim S, Kamalidehghan B, Syam S, Sue K, Saad N, et al. Involvement of NF-ï« B and Bcl2/Bax signaling pathways in the apoptosis of MCF7 cells induced by a xanthone compound pyranocycloartobiloxanthone A. Phytomedicine 2012;19:1007–15.

Nakatani K, Nakahata N, Arakawa T, Yasuda H, Ohizumi Y. Inhibition of cyclooxygenase and prostaglandin E2 synthesis by ï¡-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells. Biochem Pharmacol 2002;63:73–9.

Nakatani K, Yamakuni T, Kondo N, Arakawa T, Oosawa K, Shimura S, et al. ï§-mangostin inhibits inhibitor-B kinase activity and decreases lipopolysaccharide-induced cyclooxygenase-2 gene expression in C6 rat glioma cells. Mol Pharmacol 2004;66:667–74.

Navya A, Rayalu DJ, Devi PUM. Docking studies on xanthones of mangosteen as COX-2 inhibitors. Int J Appl Biol Pharm Technol 2011;513:263–8.

Das A, Parida P, Agarwal N, Shree J, Shankar B, Chakraborty D. (5 ’ substituted pentyloxy) xanthone derivatives as PGHS-2 inhibitors. J Appl Pharm Sci 2013;3:S13–22.

Musfiroh IDA, Muhtadi A, Kartasasmita RE, Tjahjono DH. In silico study of asiatic acid interaction with inducible nitric oxide synthase (INOS) and cyclooxygenase-2 (COX-2). Int J Pharm Pharm Sci 2013;5:204–7.

Hafeez A, Saify ZS, Naz A, Yasmin F, Akhtar N. Molecular docking study on the interaction of riboflavin (Vitamin B 2) and cyanocobalamin (Vitamin B 12) coenzymes. J Comput Med 2013.

Korb O, Stutzle T, Exner TE. Empirical scoring functions for advanced Protein-Ligand docking with PLANTS. J Chem Inf Model 2009;49:84–96.

Kartasasmita RE, Herowati R, Harmastuti N, Gusdinar T. Quercetin derivatives docking based on study of flavonoids interaction to cyclooxygenase-2docking turunan kuersetin berdasarkan studi interaksi flavonoid terhadap enzim. Indo J Chem 2009;9:297–302.

Huang S, Zou X. Efficient molecular docking of NMR structures: application to HIV-1 protease. Protein Sci 2007;16:43–51.

Prasojo SL, Agung F, Hartanto D, Yuniarti N. Docking of 1-phenylsulfonamide-3-trifluoromethyl-5-parabromophenyl-pyrazole to cyclooxygenase-2 using plants. Indo J Chem 2010;10:348–51.

DeLano WL. Review: the case for open-source software in drug discovery. Drug Discov Today 2005;10:213–7.

Habeeb AG, Rao PNP, Knaus EE. Design and synthesis of celecoxib and rofecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of sulfonamid and methylsulphonyl pharmacophores by and azido bioisostere. J Med Chem 2001;44:3039–42.

Kerr S, Gailer J. COX-2-selective NSAIDs: New wonder drugs? National Prescribing Service, New South Wale; 2010.

Zarghi A, Arfaei S. Selective COX-2 inhibitors: a review of their structure-activity relationships. Iran J Pharm Res 2011;10:655–83.

Meenambiga SS, Rajagopal K, Durga R. In silico docking studies on the components of inonotus sp., a medicinal mushroom against cyclooxygenase-2 enzyme. Asian J Pharm Clin Res 2015;8:142–5.

Kumar V, Gupta GK, Kaur K, Singh R. 4-Fluorophenylhydrazones as potential COX-2 inhibitors: a novel, efficient, one pot solid phase synthesis, docking study and pharmacological evaluation. Med Chem Res 2013;22:5890–900.

Zebardast T, Zarghi A, Daraie B, Hedayati M, Dadrass OG. Design and synthesis of 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors. Bioorg Med Chem Lett 2009;19:3162–5.

Dilber S, Dobric S, Juranic Z, Markovic B, Vladimirov S, Juranic I. Docking studies and anti-inflammatory activity. Molecules 2008;13:603–15.

Dhingra M, Deb P, Chadha R, Singh T, Karan M. Synthesis, evaluation, and molecular docking studies of cycloalkyl/and gastroprotective anti-inflammatory agents. Med Chem Res 2014;23:87–106.

Mello PD, Gadhwal MK, Joshi U, Shetgiri P. Modeling of COX-2 inhibitory activity of flavonoids. Int J Pharm Pharm Sci 2011;3:37–40.

Gautam R, Jachak SM, Kumar V, Mohan CG. Synthesis, biological evaluation and molecular docking studies of stellatin derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and anti-inflammatory agents. Bioorg Med Chem Lett 2011;21:1612–6.



How to Cite

Miladiyah, I., J. Jumina, S. M. Haryana, and M. Mustofa. “IN SILICO MOLECULAR DOCKING OF XANTHONE DERIVATIVES AS CYCLOOXYGENASE-2 INHIBITOR AGENTS”. International Journal of Pharmacy and Pharmaceutical Sciences, vol. 9, no. 3, Mar. 2017, pp. 98-104, doi:10.22159/ijpps.2017v9i3.15382.



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