Skip to main content

Dual and selective lipid inhibitors of cyclooxygenases and lipoxygenase: a molecular docking study

Abstract

The side effects of non-steroidal anti-inflammatory drugs (NSAIDs) concern the public, the government, and pharmaceutical companies. NSAIDs act as inhibitors of cyclooxygenases which are the major cause of pain and inflammation in our body. However, the inhibition of cyclooxygenases could divert arachidonic acid metabolism toward the lipoxygenase pathway leading to other forms of inflammation and tissue damage. Hence a common inhibitor that could block the action of both cyclooxygenases and lipoxygenase is of interest in medicinal chemistry research. Further, the inhibition of both cyclooxygenases-1 and 2 would result in more side effects, since blocking the action of cyclooxygenase-1 would cause gastrointestinal disturbance. Therefore, there is a need to find an inhibitor that acts on cyclooxygenase-2 and lipoxygenase without disturbing the action of cyclooxygenase-1. A molecular docking study with eight lipid ligands was conducted to find the common and selective inhibitors of these three enzymes. Docking with extra precision mode and standard precision mode was performed to find the suitable docking method using the Glide software tool. Docking with extra precision mode yielded better results than with standard precision mode. The docking results are validated using a receiver operator characteristic curve. Further, molecular dynamic simulations were performed for the docked complexes of lowest binding energies. The confirmations obtained from molecular dynamic simulations are more stable and credible than the docked confirmations. Docosahexaenoic acid, eicosapentaenoic acid, 2-arachidonyl glycerol, and anandamide are identified as dual inhibitors of cyclooxygenases and lipoxygenase. α-Tocotrienols are shown to be selective inhibitors of cyclooxygenase-2 and lipoxygenase.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15

References

  1. Aggarwal BB, Sundaram C, Prasad S, Kannappan R (2010) Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 80:1613–1631. doi:10.1016/j.bcp.2010.07.043

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  2. Balvers MG, Verhoeckx KC, Plastina P, Wortelboer HM, Meijerink J, Witkamp RF (2010) Docosahexaenoic acid and eicosapentaenoic acid are converted by 3T3-L1 adipocytes to N-acyl ethanolamines with anti-inflammatory properties. Biochim Biophys Acta 10:1107–1114. doi:10.1016/j.bbalip.2010.06.006

    Article  Google Scholar 

  3. Brash AR (1999) Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem 274:23679–23682. doi:10.1074/jbc.274.34.23679

    CAS  Article  PubMed  Google Scholar 

  4. Brown JR, DuBois RN (2005) COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol 23:2840–2855. doi:10.1200/JCO.2005.09.051

    CAS  Article  PubMed  Google Scholar 

  5. Burnett BP, Levy RM (2012) 5-Lipoxygenase metabolic contributions to NSAID-induced organ toxicity. Adv Ther. doi:10.1007/s12325-011-0100-7

  6. Deng W, Verlinde CL (2008) Evaluation of different virtual screening programs for docking in a charged binding pocket. J Chem Inf Model 48:2010–2020. doi:10.1021/ci800154w

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  7. Desmond Molecular Dynamics System version 3.1, D. E. Shaw Research, New York, NY, 2012. Maestro-Desmond Interoperability Tools, version 3.1, Schrödinger, New York, NY, 2012

  8. DeWitt DL (1999) Cox-2-selective inhibitors: the new super aspirins. Mol Pharmacol 55:625–631

    CAS  PubMed  Google Scholar 

  9. Ding XZ, Hennig R, Adrian TE (2003) Lipoxygenase and cyclooxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer. Mol Cancer 2:10. doi:10.1186/1476-4598-2-10

    PubMed Central  Article  PubMed  Google Scholar 

  10. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision Glide: docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complexes. J Med Chem 49:6177–6196

    CAS  Article  PubMed  Google Scholar 

  11. Gan TJ (2010) Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin 26:1715–1731. doi:10.1185/03007995.2010.486301

    CAS  Article  PubMed  Google Scholar 

  12. Glide (2011) Version 5.7. Schrödinger, LLC, New York

  13. Goodsell DS (2005) The molecular perspective: cyclooxygenase-2. Oncologist 5:169–171

    Article  Google Scholar 

  14. Hayes JM, Skamnaki VT, Archontis G, Lamprakis C, Sarrou J (2011) Kinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: the role of water molecules examined. Proteins 79:703–719

    CAS  Article  PubMed  Google Scholar 

  15. Huang N, Shoichet BK, Irwin JJ (2006) Benchmarking sets for molecular docking. J Med Chem 49:6789–6801. doi:10.1021/jm0608356

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  16. Hudson N, Balsitis M, Everitt S, Hawkey CJ (1993) Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut 34:742–747

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  17. Impref (2011) Impactversion 5.7. Schrodinger, LLC, New York

  18. Jonsson KO, Holt S, Fowler CJ (2006) The endocannabinoid system: current pharmacological research and therapeutic possibilities. Basic Clin Pharmacol Toxicol 2:124–134

    Article  Google Scholar 

  19. Kalva S, Vadivelan S, Jagarlapudi SARP (2011) Pharmacophore design, homology and docking studies on 5-lipoxygenase inhibitors. International Conference on Bioscience, Biochemistry and Bioinformatics, 2011, Singapore

  20. Kellenberger E, Rodrigo J, Muller P, Rognan D (2004) Comparative evaluation of eight docking tools for docking and virtual screening accuracy. Proteins 2:225–242

    Article  Google Scholar 

  21. Kronke G, Katzenbeisser J, Uderhardt S, Zaiss MM, Scholtysek C, Schabbauer G, Zarbock A, Koenders MI, Axmann R, Zwerina J, Baenckler HW, van den Berg W, Voll RE, Kühn H, Joosten LA, Schett G (2009) 12/15-Lipoxygenase counteracts inflammation and tissue damage in arthritis. J Immunol 183:3383–3389. doi:10.4049/jimmunol.0900327

    Article  PubMed  Google Scholar 

  22. Kuhn H (2005) Biologic relevance of lipoxygenase isoforms in atherogenesis. Expert Rev Cardiovasc Ther 3:1099–1110. doi:10.1586/14779072.3.6.1099

    CAS  Article  PubMed  Google Scholar 

  23. Laufer S (2001) Discovery and development of ML 3000. Inflammopharmacology 9:101–112

    CAS  Article  Google Scholar 

  24. Leval XD, Julemont F, Delarge J, Pirotte B, Dogne JM (2002) New trends in dual 5-LOX/COX inhibition. Curr Med Chem 9:941–962

    Article  PubMed  Google Scholar 

  25. LigPrep (2011) Version 2.5. Schrödinger, LLC, New York, NY

  26. Maestro (2011) Version 9.2. Schrödinger, LLC, New York, NY

  27. Matsuyama M, Yoshimura R (2009) Arachidonic acid pathway: a molecular target in human testicular cancer (review). Mol Med Rep 2:527–531. doi:10.3892/mmr_00000131

    CAS  PubMed  Google Scholar 

  28. Perola E, Walters WP, Charifson PS (2004) A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance. Proteins 2:235–249

    Article  Google Scholar 

  29. Rainsford KD (1987) The effects of 5-lipoxygenase inhibitors and leukotriene antagonists on the development of gastric lesions induced by nonsteroidal antiinflammatory drugs in mice. Agents Actions 21:316–319

    CAS  Article  PubMed  Google Scholar 

  30. Rainsford KD (1999a) Leukotrienes in the pathogenesis of NSAID-induced gastric and intestinal mucosal damage. Agents Actions 39:24–26

    Article  Google Scholar 

  31. Rainsford KD (1999b) Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Am J Med 107:27–35. doi:10.1016/S0002-9343(99)00365-4

    Article  Google Scholar 

  32. Randy CM, Don WP (2001) Cyclooxygenases. Med Pub. http://www.medpubinc.com/newsletters/RPL.pdf. Accessed 15 Nov 2012

  33. Shu M, Lin Z, Zhang Y, Wu Y, Mei H et al (2011) Molecular dynamicssimulation of oseltamivir resistance in neuraminidase of avian influenza H5N1 virus. J Mol Model 17:587–592

    CAS  Article  PubMed  Google Scholar 

  34. Shureiqi I, Lippman SM (2001) Lipoxygenase modulation to reverse carcinogenesis. Cancer Res 61:6307–6312

    CAS  PubMed  Google Scholar 

  35. Shureiqi I, Chen D, Lee JJ, Yang P, Newman RA, Brenner DE, Lotan R, Fischer SM, Lippman SM (2012) 15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells. J Natl Cancer Inst 92:1136–1142

    Article  Google Scholar 

  36. Sidhu RS, Lee JY, Yuan C, Smith WL (2010) Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry 33:7069–7079. doi:10.1021/bi1003298

    Article  Google Scholar 

  37. Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182. doi:10.1146/annurev.biochem.69.1.145

    CAS  Article  PubMed  Google Scholar 

  38. Subbaramaiah K, Dannenberg AJ (2003) Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 24:96–102. doi:10.1016/S0165-6147(02)00043-3

    Google Scholar 

  39. Sun Y, Bennett A (2007) Cannabinoids: a new group of agonists of PPARs. PPAR Res 2007. doi:10.1155/2007/23513

  40. Vane JR, Bakhle YS, Botting RM (1998) Cyclooxygenases 1 and 2. Annu Rev Pharm Toxicol 38:97–120. doi:10.1146/annurev.pharmtox.38.1.97

    CAS  Article  Google Scholar 

  41. Wei D, Christophe LMJV (2008) Evaluation of different virtual screening programs for docking in a charged binding pocket. J Chem Inf Model 48:2010–2020. doi:10.1021/ci800154w

    Article  Google Scholar 

  42. Zheng M, Zhang Z, Zhu W, Liu H, Luo X, Chen K, Jiang H (2006) Essential structural profile of a dual functional inhibitor against cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX): molecular docking and 3D-QSAR analyses on DHDMBF analogues. Bioorg Med Chem 14:3428–3437. doi:10.1016/j.bbr.2011.03.031

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Victoria University and Bharathidasan University for providing the facilities needed for the study. We would like to thank Abdulrahman Hadbah for the technical support provided.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Rajyalakshmi S. Gaddipati.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gaddipati, R.S., Raikundalia, G.K. & Mathai, M.L. Dual and selective lipid inhibitors of cyclooxygenases and lipoxygenase: a molecular docking study. Med Chem Res 23, 3389–3402 (2014). https://doi.org/10.1007/s00044-014-0919-y

Download citation

Keywords

  • COX-1
  • COX-2
  • LOX
  • Glide docking
  • ROC curve
  • Molecular dynamics simulation