Computer search for molecular mechanisms of ulcerogenic action of non-steroidal anti-inflammatory drugs

  • S. M. Ivanov
  • A. A. Lagunin
  • A. V. Zakharov
  • D. A. Filimonov
  • V. V. Poroikov
Article

Abstract

Peptic ulcers are the most frequent side effect of therapy with non-steroidal anti-inflammatory drugs (NSAIDs). Good experimental evidence exists that pathogenesis of peptic ulcers cannot be attributed only to inhibition of cyclooxygenases. The knowledge about other molecular mechanisms of drug action associated with development of peptic ulcers could be useful for design of new safer NSAIDs. However, considerable time and material resources are needed for corresponding experimental studies. For simplification of the experimental search, we have developed an approach for in silico identification of putative molecular mechanisms of drug actions associated with their side effects. We have generated a data set of 85 NSAIDs, which includes information about their structures and side effects. Unknown molecular mechanisms of action of these NSAIDs were evaluated by the computer program PASS (Prediction of Activity Spectra for Substances) predicting more than 3000 molecular mechanisms of action based on structural formula of sub-stances. Statistically significant associations have been found between predicted molecular mechanisms of action and development of peptic ulcers. Twenty six molecular mechanisms of action probably associated with development of peptic ulcers have been found: two of them were known previously and 24 were quite new. Analyzing Gene Ontology data, data on signal and metabolic pathways, and available MEDLINE publication data, we proposed hypotheses on the role of 10 molecular mechanisms of action in the pathogenesis of peptic ulcer.

Keywords

non-steroidal anti-inflammatory drugs peptic ulcers molecular mechanisms of action computer-aided drug design 

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References

  1. 1.
    Al Mofleh, I.A. and Al Rashed, R.S., Saudi J. Gastroenterol., 2007, vol. 13, no. 3, pp. 107–113.CrossRefGoogle Scholar
  2. 2.
    Musumba, C., Pritchard, D.M., and Pirmohamed, M., Aliment. Pharmacol. Ther., 2009, vol. 30, pp. 517–531.CrossRefGoogle Scholar
  3. 3.
    Suleyman, H., Albayrak, A., Bilici, M., Cadirci, E., and Halici, Z., Inflammation, 2010, vol. 33, no. 4, pp. 224–234.CrossRefGoogle Scholar
  4. 4.
    Salvo, F., Fourrier-Réglat, A., Bazin, F., Robinson, P., Riera-Guardia, N., Haag, M., Caputi, A.P., Moore, N., Sturkenboom, M.C., and Pariente, A., Clin. Pharmacol. Ther., 2011, vol. 89, pp. 855–866.CrossRefGoogle Scholar
  5. 5.
    Schubert, M.L., Curr. Opin. Gastroenterol., 2000, vol. 16, pp. 463–468.CrossRefGoogle Scholar
  6. 6.
    Whitebread, S., Hamon, J., Bojanic, D., and Urban, L., Drug Discov. Today, 2005, vol. 10, pp. 1421–1433.CrossRefGoogle Scholar
  7. 7.
    Filimonov, D.A. and Poroikov, V.V., Rus. Khim. Zhurn., 2006, vol. 50, no. 2, pp. 66–75.Google Scholar
  8. 8.
    Filimonov, D.A. and Poroikov, V.V., in Chemoinformatics Approaches to Virtual Screening, Varnek, A. and Tropsha, A., Eds., Cambridge (UK): RSC Publishing, 2008, pp. 182–216.Google Scholar
  9. 9.
    Vogt, A., Tamura, K., Watson, S., and Lazo, J.S., J. Pharmacol. Exp. Ther., 2000, vol. 294, pp. 1070–1075.Google Scholar
  10. 10.
    Mitchell, D.A., Morton, S.U., Fernhoff, N.B., and Marletta, M.A., Proc. Natl. Acad. Sci. USA, 2007, vol. 104, no. 28, pp. 11609–11614.CrossRefGoogle Scholar
  11. 11.
    Watson, W.H., Yang, X., Choi, Y.E., Jones, D.P., and Kehrer, J.P., Toxicol. Sci., 2004, vol. 78, no. 1, pp. 3–14.CrossRefGoogle Scholar
  12. 12.
    Pallis, M., Bradshaw, T.D., Westwell, A.D., Grundy, M., Stevens, M.F., and Russell, N., Biochem. Pharmacol., 2003, vol. 66, pp. 1695–1705.CrossRefGoogle Scholar
  13. 13.
    Tan, A., Nakamura, H., Kondo, N., Tanito, M., et al., Free Radic. Res., 2007, vol. 41, pp. 861–869.CrossRefGoogle Scholar
  14. 14.
    Peskar, B.M., Ehrlich, K., Schuligoi, R., and Peskar, B.A., Pharmacology, 2009, vol. 84, no. 5, pp. 294–299.CrossRefGoogle Scholar
  15. 15.
    Hernandez, D.E., Walker, C.H., and Mason, G.A., Life Sci., 1988, vol. 42, pp. 1757–1764.CrossRefGoogle Scholar
  16. 16.
    Samuels, M.H., Pillote, K., Asher, D., and Nelson, J.C., J. Clin. Endocrinol. Metab., 2003, vol. 88, pp. 5710–5716.CrossRefGoogle Scholar
  17. 17.
    Filaretova, L., Bagaeva, T., and Makara, G.B., Life Sci., 2002, vol. 71, pp. 2457–2468.CrossRefGoogle Scholar
  18. 18.
    Maruyama, K., Okazaki, I., Arai, M., Kurose, I., Komatsu, H., Nakamura, M., and Tsuchiya, M., J. Gastroenterol., 1995, vol. 30, no. 3, pp. 301–309.CrossRefGoogle Scholar
  19. 19.
    Bingle, C.D., Craig, R.W., Swales, B.M., Singleton, V., Zhou, P., and Whyte, M.K., J. Biol. Chem., 2000, vol. 275, pp. 22136–22146.CrossRefGoogle Scholar
  20. 20.
    Kim, N., Yoo, J.C., Han, J.Y., Hwang, E.M., Kim, Y.S., Jeong, E.Y., Sun, C.H., Yi, G.S., Roh, G.S., Kim, H.J., Kang, S.S., Cho, G.J., Park, J.Y., and Choi, W.S., J. Cell. Physiol., 2012, vol. 227, pp. 1157–1167.CrossRefGoogle Scholar
  21. 21.
    Ong, C.C., Jubb, A.M., Haverty, P.M., Zhou, W., Tran, V., Truong, T., Turley, H., O’Brien, T., Vucic, D., Harris, A.L., Belvin, M., Friedman, L.S., Black-wood, E.M., Koeppen, H., Hoeflich, K.P., Proc. Natl. Acad. Sci. USA, 2011, vol. 108, pp. 7177–7182.CrossRefGoogle Scholar
  22. 22.
    Hamel, E., Biopolymers, 2002, vol. 66, no. 3, pp. 142–160.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2013

Authors and Affiliations

  • S. M. Ivanov
    • 1
  • A. A. Lagunin
    • 1
  • A. V. Zakharov
    • 1
  • D. A. Filimonov
    • 1
  • V. V. Poroikov
    • 1
  1. 1.Orekhovich Institute of Biomedical Chemistry of Russian Academy of Medical SciencesMoscowRussia

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