Molecular docking studies of curcumin natural derivatives with DNA topoisomerase I and II-DNA complexes

  • Anil Kumar
  • Utpal Bora
Original Article


DNA topoisomerase I (topo I) and II (topo II) are essential enzymes that solve the topological problems of DNA by allowing DNA strands or double helices to pass through each other during cellular processes such as replication, transcription, recombination, and chromatin remodeling. Their critical roles make topoisomerases an attractive drug target against cancer. The present molecular docking study provides insights into the inhibition of topo I and II by curcumin natural derivatives. The binding modes suggested that curcumin natural derivatives docked at the site of DNA cleavage parallel to the axis of DNA base pairing. Cyclocurcumin and curcumin sulphate were predicted to be the most potent inhibitors amongst all the curcumin natural derivatives docked. The binding modes of cyclocurcumin and curcumin sulphate were similar to known inhibitors of topo I and II. Residues like Arg364, Asn722 and base A113 (when docked to topo I-DNA complex) and residues Asp479, Gln778 and base T9 (when docked to topo II-DNA complex) seem to play important role in the binding of curcumin natural derivatives at the site of DNA cleavage.

Key words

curcumin natural derivatives DNA topoisomerases cancer drug target molecular docking polar interactions autodock 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Anand, P., Sundaram, C., Jhurani, S., Kunnumakkara, A.B., Aggarwal, B.B. 2008b. Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett 267, 133–164.PubMedCrossRefGoogle Scholar
  2. [2]
    Anand, P., Thomas, S.G., Kunnumakkara, A.B., Sundaram, C., Harikumar, K.B. et al. 2008a. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol 76, 1590–1611.PubMedCrossRefGoogle Scholar
  3. [3]
    Baird, C.L., Gordon, M.S., Andrenyak, D.M., Marecek, J.F., Lindsley, J.E. 2001. The ATPase reaction cycle of yeast DNA topoisomerase II. Slow rates of ATP resynthesis and P(i) release. J Biol Chem 276, 27893–27898.PubMedCrossRefGoogle Scholar
  4. [4]
    Beck, L.S., Deguzman, L., Lee, W.P., Xu, Y., Siegel, M.W., Amento, E.P. 1993. One systemic administration of transforming growth factor-beta 1 reverses ageor glucocorticoid-impaired wound healing. J Clin Invest 92, 2841–2849.PubMedCentralPubMedCrossRefGoogle Scholar
  5. [5]
    Belani, C.P., Doyle, L.A., Aisner, J. 1994. Etoposide: Current status and future perspectives in the management of malignant neoplasms. Cancer Chemoter Pharmacol 34, 1180–1126.CrossRefGoogle Scholar
  6. [6]
    Champoux, J.J. 2000. Structure-based analysis of the effects of camptothecin on the activities of human topoisomerase I. Ann, N.Y., Acad Sci 922, 56–64.CrossRefGoogle Scholar
  7. [7]
    Champoux, J.J. 2001. DNA topoisomerases: Structure, function, and mechanism. Annu Rev Biochem 70, 369–413.PubMedCrossRefGoogle Scholar
  8. [8]
    Chow, K.C., Macdonald, T.L., Ross, W.E. 1988. DNA binding by epipodophyllotoxins and N-acyl anthracyclines: Implications for mechanism of topoisomerase inhibition. Mol Pharmacol 34, 467–473.PubMedGoogle Scholar
  9. [9]
    Gellert, M. 1981. DNA topoisomerases. Annu Rev Biochem 50, 879–910.PubMedCrossRefGoogle Scholar
  10. [10]
    Gupta, E., Mick, R., Ramirez, J., Wang, X., Lestingi, T.M., Vokes, E.E., Ratain, M.J. 1997. Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 15, 1502–1510.PubMedGoogle Scholar
  11. [11]
    Kumar, A., Bora, U. 2011. In silico inhibition studies of NF-κB p50 subunit by curcumin and its natural derivatives. Med Chem Res. doi:110.1007/s00044-011-9873-0.Google Scholar
  12. [12]
    Lin, J.K. 2007. Molecular targets of curcumin. Adv Exp Med Biol 595, 227–243.PubMedCrossRefGoogle Scholar
  13. [13]
    López-Lázaro, M., Willmore, E., Jobson, A., Gilroy, K.L., Curtis, H., Padget, K., Austin, C.A. 2007. Curcumin induces high levels of topoisomerase I- and II-DNA complexes in K562 leukemia cells. J Nat Prod 70, 1884–1888.PubMedCrossRefGoogle Scholar
  14. [14]
    Maheshwari, R.K., Singh, A.K., Gaddipati, J., Srimal, R.C. 2006. Multiple biological activities of curcumin: a short review. Life Sci 78, 2081–2087.PubMedCrossRefGoogle Scholar
  15. [15]
    Martín-Cordero, C., López-Lázaro, M., Gálvez, M., Ayuso, M.J. 2003. Curcumin as a DNA topoisomerase II poison. J Enzyme Inhib Med Chem 18, 505–509.PubMedCrossRefGoogle Scholar
  16. [16]
    Morris, G.M., Goodsell, G.S., Halliday, R.S., Huey, R., Hart, W.E. et al. 1998. Automated docking using Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 19, 1639–1662.CrossRefGoogle Scholar
  17. [17]
    Mosieniak, G., Sliwinska, M., Piwocka, K., Sikora, E. 2006. Curcumin abolishes apoptosis resistance of calcitriol-differentiated HL-60 cells. FEBS Lett 580, 4653–4660.PubMedCrossRefGoogle Scholar
  18. [18]
    Osheroff, N. 1989. Effect of antineoplastic agents on the DNA cleavage/religation equlibrium of eukaryotic topoisomerase II: Inhibition of DNA religation by etoposide. Biochemistry 28, 6157–6160.PubMedCrossRefGoogle Scholar
  19. [19]
    Robinson, H.M., Bratlie-Thoresen, S., Brown, R., Gillespie, D.A. 2007. Chk1 is required for G2/M checkpoint response induced by the catalytic topoisomerase II inhibitor ICRF-193. Cell Cycle 6, 1265–1267.PubMedCrossRefGoogle Scholar
  20. [20]
    Salerno, S., Da Settimo, F., Taliani, S., Simorini, F., La Motta, C., Fornaciari, G., Marini, A.M. 2010. Recent advances in the development of dual topoisomerase I and II inhibitors as anticancer drugs. Curr Med Chem 17, 4270–4290.PubMedCrossRefGoogle Scholar
  21. [21]
    Sanner, M.F. 1999. Python: a programming language for software integration and development. J Mol Graph Model 17, 57–61.PubMedGoogle Scholar
  22. [22]
    Staker, B.L., Hjerrild, K., Feese, M.D., Behnke, C.A. et al. 2002. The mechanism of topoisomerase I poisoning by a camptothecin analog. PNAS 99, 15387–15392.PubMedCentralPubMedCrossRefGoogle Scholar
  23. [23]
    Wang, J.C. 1985. DNA topoisomerases. Annu Rev Biochem 54, 665–697.PubMedCrossRefGoogle Scholar
  24. [24]
    Wang, J.C. 2002. Cellular roles of DNA topoisomerases: A molecular perspective. Nat Rev Mol Cell Biol 3, 430–440.PubMedCrossRefGoogle Scholar

Copyright information

© International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Computational Biology Laboratory, Department of BiotechnologyIndian Institute of Technology GuwahatiGuwahatiIndia
  2. 2.DBT Biotech Hub, Centre for the EnvironmentIndian Institute of Technology GuwahatiGuwahatiIndia

Personalised recommendations