PHARMACOPHORE SCREENING AND MOLECULAR DOCKING OF PHYTOCONSTITUENTS IN POLYGONUM SAGITTATUM FOR CYCLOOXYGENASE-2 INHIBITORS DISCOVERY.
Â Objective: The objective of this study is to discover cyclooxygenase (COX-2) inhibitors from Polygonum sagittatum (Polygonaceae), by screening the pharmacophores based on the interaction of mefenamic acid with COX-2, followed by molecular docking with COX-2.
Methods: The protein crystal structure of human COX-2 in complex with mefenamic acid (PDB code: 5IKR) was selected, its ligand-protein interaction was studied by employing LigandScout to obtain the pharmacophore features. The features were validated against PGH2 database provided at http://dude.docking.org/targets/pgh2, and the result was used to screen the pharmacophores of the phytoconstituents isolated from P. sagittatum. Furthermore, a molecular docking of the phytoconstituents into COX-2 binding pocket was performed. The compounds were generated using MarvinSketch, and the energy was optimized by employing LigandScout MMFF94. Celecoxib and mefenamic acid, selective COX-2 inhibitors, were used as the standard drugs.
Results: The pharmacophore features obtained were aromatic ring (hydrophobicity) and two hydrogen bond acceptors, which are proved valid against PGH2 training set (GH score = 0.78; AUC100% receiver operating characteristic curve = 0.97). There are four phytoconstituents (quercetin, protocatechuic acid, vanicoside A, and vanicoside B) that fit the features, and therefore, are predicted to be active in inhibiting COX-2. The docking reveals that three phytoconstituents (methyl-4-hydroxycinnamate, quercetin, and methyl gallate) interact with Tyr385, an important amino acid residue in COX-2 binding pocket. Quercetin is the best in inhibiting the enzyme (docking score âˆ’8.60 kcal/mol; inhibition constant 0.5 Î¼M), compared to mefenamic acid (docking score âˆ’8.90 kcal/mol; inhibition constant 0.3 Î¼M) and celecoxib (docking score âˆ’10.00 kcal/mol; inhibition constant 0.05 Î¼M).
Conclusions: Phytoconstituents in P. sagittatum fit the pharmacophore features generated from mefenamic acid and COX-2 complex; therefore, they might be potential in inhibiting COX-2 enzyme. Their binding modes are more similar to that of mefenamic acid than of celecoxib. Of those, quercetin is the best in inhibiting the enzyme. Its inhibitory activity is equal to mefenamic acid but is weaker than celecoxib.
2. Mazid MA, Datta BK, Nahar L, Bashar SA, Bachar SC, Sarker SD. Antinociceptive, anti-inflammatory and diuretic properties of Polygonum barbatum (L.) Hara var. Barbata. Rev Bras Farmacogn 2009;19:749-54.
3. Sahidin I, Suwandi A, Nohong N, Manggau MA. Profile of anticancer and radical scavenging activities of steroids from stems of Polygonum pulchrum. Int J Pharm Sci Res 2015;6(5):2178-84.
4. Kimura Y, Okuda H. Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinoma-bearing mice. J Nutr 2001;131:1844-9.
5. Lin YW, Yang FJ, Chen CL, Lee WT, Chen RS. Free radical scavenging activity and anti-proliferative potential of Polygonum cuspidatum root extracts. J Nat Med 2010;64:146-52.
6. El-Toumy SA, Salib JY, Shafik NH, Elkarim AS, Mick GA. New flavonoids from the aerial parts of Polygonum equisetiforme SM (Polygonaceae). Int J Pharm Pharm Sci 2017;9:166-70.
7. Zhong Y, Yoshinaka Y, Takeda T, Shimizu N, Yoshizaki S, Inagaki Y, et al. Highly potent anti-HIV-1 activity isolated from fermented Polygonum tinctorium Aiton. Antiviral Res 2005;66:119-28.
8. Datta B, Datta S, Khan T, Kundu J, Rashid M, Nahar L, et al. Anti-cholinergic, cytotoxic and anti-HIV-1 activities of sesquiterpenes and a flavonoid glycoside from the aerial parts of Polygonum viscosum. Pharm Biol 2004;42:18-23.
9. Leu YL, Hwang TL, Hu JW, Fang JY. Anthraquinones from Polygonum cuspidatum as tyrosinase inhibitors for dermal use. Phytother Res 2008;22:552-6.
10. Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surg Neurol Int 2010;1:80.
11. Elmali N, Baysal O, Harma A, Esenkaya I, Mizrak B. Effects of resveratrol in inflammatory arthritis. Inflammation 2007;30:1-6.
12. Hasanah AN, Levita J, Natapoera ED, Subarnas A. Analyzing the interaction of shellegueain A, a bioactive compound of Pakis tangkur (Selliguea feei or Polypodium feei) to cyclooxygenase enzyme bymolecular docking. Asian J Chem 2011;23:3093-6.
13. Saptarini NM, Sitorus EY, Levita J. Structure-based in silico study of 6-gingerol, 6-shogaol, and 6-paradol, active compounds of ginger (Zingiber officinale) as COX-2 inhibitors. Int J Chem 2013;5:12-8.
14. ValdÃ©s-Barrera ID, Cuca-Suarez LE, Coy-Barrera ED. Nectandra amazonum-derived flavonoids as COX-1 inhibitors: In vitro and docking studies. Nat Prod Commun 2014;9:649-52.
15. Dash R, Uddin MM, Hosen SM, Rahim ZB, Dinar AM, Kabir MS, et al. Molecular docking analysis of known flavonoids as duel COX-2 inhibitors in the context of cancer. Bioinformation 2015;11:543-9.
16. Orlando BJ, Malkowski MG. Substrate-selective Inhibition of cyclooxygeanse-2 by fenamic acid derivatives is dependent on peroxide tone. J Biol Chem 2016;291:15069-81.
17. Sahidin I, Manggau MA, Widodo H. Secondary metabolites isolated from Polygonum sagittatum. Under Rev.
18. Niu MM, Qin JY, Tian CP, Yan XF, Dong FG, Cheng ZQ, et al. Tubulin inhibitors: Pharmacophore modeling, virtual screening and molecular docking. Acta Pharmacol Sin 2014;35:967-79.
19. Niu M, Dong F, Tang S, Fida G, Qin J, Qiu J, et al. Pharmacophore modeling and virtual screening for the discovery of new Type 4 camp phosphodiesterase (PDE4) inhibitors. PLoS One 2013;8:e82360.
20. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 1998;104:413-21.
21. Prusakiewicz JJ, Duggan KC, Rouzer CA, Marnett LJ. Differential sensitivity and mechanism of inhibition of COX-2 oxygenation of arachidonic acid and 2-arachidonoylglycerol by ibuprofen and mefenamic acid. Biochemistry 2009;48:7353-5.
22. Kartasasmita RE, Herowati R, Harmastuti N, Gusdinar T. Quercetin derivatives docking based on study of flavonoids interaction to cyclooxygenase-2. Indo J Chem 2009;9:297-302.
23. Kumar V, Gupta GK, Kaur K, Singh R. 4-Fluorophenyl-hydrazones 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.
24. Miladiyah I, Jumina J, Haryana SM, Mustofa M. In silico molecular docking of xanthone derivatives as cyclooxygenase-2 inhibitor agents. Int J Pharm Pharm Sci 2017;9:98-104.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.