Protein & Cell

, Volume 3, Issue 2, pp 132–139 | Cite as

Study of drug function based on similarity of pathway fingerprint

  • Hao Ye
  • Kailin Tang
  • Linlin Yang
  • Zhiwei Cao
  • Yixue LiEmail author
Research Article


Drugs sharing similar therapeutic function may not bind to the same group of targets. However, their targets may be involved in similar pathway profiles which are associated with certain pathological process. In this study, pathway fingerprint was introduced to indicate the profile of significant pathways being influenced by the targets of drugs. Then drug-drug network was further constructed based on significant similarity of pathway fingerprints. In this way, the functions of a drug may be hinted by the enriched therapeutic functions of its neighboring drugs. In the test of 911 FDA approved drugs with more than one known target, 471 drugs could be connected into networks. 760 significant associations of drug-therapeutic function were generated, among which around 60% of them were supported by scientific literatures or ATC codes of drug functional classification. Therefore, pathway fingerprints may be useful to further study on the potential function of known drugs, or the unknown function of new drugs.


pathway fingerprint drug-drug network therapeutic target function prediction 

Supplementary material

13238_2012_2011_MOESM1_ESM.xls (326 kb)
Supplementary material, approximately 325 KB.


  1. Adams, C.P., and Brantner, V.V. (2006). Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood) 25, 420–428.CrossRefGoogle Scholar
  2. Anandarajah, A.P., Schwarz, E.M., Totterman, S., Monu, J., Feng, C.Y., Shao, T., Haas-Smith, S.A., and Ritchlin, C.T. (2008). The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis. Ann Rheum Dis 67, 296–301.CrossRefPubMedGoogle Scholar
  3. Andraos, J. (2008). Kinetic plasticity and the determination of product ratios for kinetic schemes leading to multiple products without rate laws: new methods based on directed graphs. Can J Chem 86, 342–357.CrossRefGoogle Scholar
  4. Azzoli, C.G., Krug, L.M., Miller, V.A., Kris, M.G., and Mass, R. (2002). Trastuzumab in the treatment of non-small cell lung cancer. Semin Oncol 29, 59–65.CrossRefPubMedGoogle Scholar
  5. Barabási, A.L., and Oltvai, Z.N. (2004). Network biology: understanding the cell’s functional organization. Nat Rev Genet 5, 101–113.CrossRefPubMedGoogle Scholar
  6. Chen, L., Feng, K.Y., Cai, Y.D., Chou, K.C., and Li, H.P. (2010). Predicting the network of substrate-enzyme-product triads by combining compound similarity and functional domain composition. BMC Bioinformatics 11, 293.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Chong, C.R., and Sullivan, D.J. Jr. (2007). New uses for old drugs. Nature 448, 645–646.CrossRefPubMedGoogle Scholar
  8. Chou, K.C. (1989). Low-frequency resonance and cooperativity of hemoglobin. Trends Biochem Sci 14, 212–213.CrossRefPubMedGoogle Scholar
  9. Chou, K.C. (1995). A novel approach to predicting protein structural classes in a (20-1)-D amino acid composition space. Proteins 21, 319–344.CrossRefPubMedGoogle Scholar
  10. Chou, K.C. (1996). Review: Prediction of HIV protease cleavage sites in proteins. Anal Biochem 233, 1–14.CrossRefPubMedGoogle Scholar
  11. Chou, K. C. (2001). Prediction of protein cellular attributes using pseudo amino acid composition. PROTEINS: Structure, Function, and Genetics (Erratum: ibid, 2001, 44, 60) 43, 246–255.CrossRefGoogle Scholar
  12. Chou, K.C. (2010). Graphic rule for drug metabolism systems. Curr Drug Metab 11, 369–378.CrossRefPubMedGoogle Scholar
  13. Chou, K.C., and Shen, H.B. (2007). Signal-CF: a subsite-coupled and window-fusing approach for predicting signal peptides. Biochem Biophys Res Commun 357, 633–640.CrossRefPubMedGoogle Scholar
  14. Chou, K.C., Wu, Z.C., and Xiao, X. (2011). iLoc-Euk: a multi-label classifier for predicting the subcellular localization of singleplex and multiplex eukaryotic proteins. PLoS One 6, e18258.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Deitchman, D., Braselton, J.P., Hayes, D.C., and Stratman, R.L. (1980). The ganglion-blocked, angiotensin II-supported rat: a model for demonstrating antihypertensive vasodilator activity. J Pharmacol Methods 3, 311–321.CrossRefPubMedGoogle Scholar
  16. Delord, J.P., Quideau, S., Rochaix, P., Caselles, O., Couderc, B., Hennebelle, I., Courbon, F., Canal, P., and Allal, B.C. (2010). Trastuzumab induced in vivo tissue remodelling associated in vitro with inhibition of the active forms of AKT and PTEN and RhoB induction in an ovarian carcinoma model. Br J Cancer 103, 61–72.PubMedCentralCrossRefPubMedGoogle Scholar
  17. Fintini, D., Brufani, C., and Cappa, M. (2009). Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin Risk Manag 5, 553–559.PubMedCentralPubMedGoogle Scholar
  18. Fodor, M. (2011). [Current views on the metabolic syndrome and the effects of antipsychotic drugs]. Psychiatr Hung 26, 196–200.PubMedGoogle Scholar
  19. He, Z., Zhang, J., Shi, X.H., Hu, L.L., Kong, X., Cai, Y.D., and Chou, K.C. (2010). Predicting drug-target interaction networks based on functional groups and biological features. PLoS One 5, e9603.PubMedCentralCrossRefPubMedGoogle Scholar
  20. Hu, L.L., Chen, C., Huang, T., Cai, Y.D., and Chou, K.C. (2011a). Predicting biological functions of compounds based on chemical-chemical interactions. PLoS One 6, e29491.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Hu, L.L., Huang, T., Cai, Y.D., and Chou, K.C. (2011b). Prediction of body fluids where proteins are secreted into based on protein interaction network. PLoS One 6, e22989.PubMedCentralCrossRefPubMedGoogle Scholar
  22. Huang, T., Shi, X.H., Wang, P., He, Z., Feng, K.Y., Hu, L., Kong, X., Li, Y.X., Cai, Y.D., and Chou, K.C. (2010). Analysis and prediction of the metabolic stability of proteins based on their sequential features, subcellular locations and interaction networks. PLoS One 5, e10972.PubMedCentralCrossRefPubMedGoogle Scholar
  23. Huang, W., Sherman, B.T., and Lempicki, R.A. (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4, 44–57.CrossRefGoogle Scholar
  24. Kamikawa, Y., and Shimo, Y. (1987). Different spasmolytic effects of smooth muscle relaxants on the guinea-pig esophageal muscularis mucosae contracted by carbachol or high potassium in vitro. Eur J Pharmacol 136, 39–48.CrossRefPubMedGoogle Scholar
  25. Kanehisa, M., Goto, S., Furumichi, M., Tanabe, M., and Hirakawa, M. (2010). KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res 38, D355–D360.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Keating, G.M. (2008). Mecasermin. BioDrugs 22, 177–188.CrossRefPubMedGoogle Scholar
  27. Knox, C., Law, V., Jewison, T., Liu, P., Ly, S., Frolkis, A., Pon, A., Banco, K., Mak, C., Neveu, V., et al. (2011). DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs. Nucleic Acids Res 39, D1035–D1041.PubMedCentralCrossRefPubMedGoogle Scholar
  28. Kondo, N., Ishiguro, Y., Kimura, M., Sano, D., Fujita, K., Sakakibara, A., Taguchi, T., Toth, G., Matsuda, H., and Tsukuda, M. (2008). Antitumor effect of gefitinib on head and neck squamous cell carcinoma enhanced by trastuzumab. Oncol Rep 20, 373–378.PubMedGoogle Scholar
  29. Krantz, A. (1998). Protein-site targeting. Diversification of the drug discovery process. Nat Biotechnol 16, 1294.CrossRefPubMedGoogle Scholar
  30. Lazner, F., Gowen, M., Pavasovic, D., and Kola, I. (1999). Osteopetrosis and osteoporosis: two sides of the same coin. Hum Mol Genet 8, 1839–1846.CrossRefPubMedGoogle Scholar
  31. Liao, C.H., Chang, C.S., Wei, W.C., Chang, S.N., Liao, C.C., Lane, H.Y., and Sung, F.C. (2011). Schizophrenia patients at higher risk of diabetes, hypertension and hyperlipidemia: a population-based study. Schizophr Res 126, 110–116.CrossRefPubMedGoogle Scholar
  32. Mineo, J.F., Bordron, A., Quintin-Roué, I., Loisel, S., Ster, K.L., Buhé, V., Lagarde, N., and Berthou, C. (2004). Recombinant humanized anti-HER2/neu antibody (Herceptin) induces cellular death of glioblastomas. Br J Cancer 91, 1195–1199.PubMedCentralPubMedGoogle Scholar
  33. Nacher, J.C., and Schwartz, J.M. (2008). A global view of drug-therapy interactions. BMC Pharmacol 8, 5.PubMedCentralCrossRefPubMedGoogle Scholar
  34. Timberlake, W.H., and Schwab, R.S. (1952). Experimental preparation W-483 in the treatment of Parkinson’s disease. N Engl J Med 247, 98–100.CrossRefPubMedGoogle Scholar
  35. Tobinick, E.L. (2009). The value of drug repositioning in the current pharmaceutical market. Drug News Perspect 22, 119–125.CrossRefPubMedGoogle Scholar
  36. Wermuth, C.G. (2004). Multitargeted drugs: the end of the “one-target-one-disease” philosophy? Drug Discov Today 9, 826–827.CrossRefPubMedGoogle Scholar
  37. Willett, P., Barnard, J.M., and Downs, G.M. (1998). Chemical similarity searching. J Chem Inf Comput Sci 38, 983–996.CrossRefGoogle Scholar
  38. Xiao, X., Lin, W.Z., and Chou, K.C. (2008). Using grey dynamic modeling and pseudo amino acid composition to predict protein structural classes. J Comput Chem 29, 2018–2024.CrossRefPubMedGoogle Scholar
  39. Xiao, X., Wang, P., and Chou, K.C. (2009). GPCR-CA: A cellular automaton image approach for predicting G-protein-coupled receptor functional classes. J Comput Chem 30, 1414–1423.CrossRefPubMedGoogle Scholar
  40. Yildirim, M.A., Goh, K.I., Cusick, M.E., Barabási, A.L., and Vidal, M. (2007). Drug-target network. Nat Biotechnol 25, 1119–1126.CrossRefPubMedGoogle Scholar
  41. Zhou, G.P., and Deng, M.H. (1984). An extension of Chou’s graphic rules for deriving enzyme kinetic equations to systems involving parallel reaction pathways. Biochem J 222, 169–176.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Hao Ye
    • 1
    • 2
  • Kailin Tang
    • 2
  • Linlin Yang
    • 1
    • 2
  • Zhiwei Cao
    • 3
  • Yixue Li
    • 1
    • 2
    Email author
  1. 1.State Key Laboratory of Bioreactor EngineeringEast China University of Science & TechnologyShanghaiChina
  2. 2.Shanghai Center for Bioinformation TechnologyShanghaiChina
  3. 3.School of Life Science and TechnologyTongji UniversityShanghaiChina

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