Binding Mode and Inhibitory Activity of Constituents Isolated from Sclerotium of Poria cocos with DNA Topoisomerase I

Poria cocos 균핵에서 분리한 성분들과 DNA Topoisomerase I의 반응양상 및 효소저해 활성

  • Choi, Inhee (College of Pharmacy, Ewha Womans University) ;
  • Kim, Ji-Hyun (College of Pharmacy, Ewha Womans University) ;
  • Kim, Choonmi (College of Pharmacy, Ewha Womans University)
  • 최인희 (이화여자대학교 약학대학) ;
  • 김지현 (이화여자대학교 약학대학) ;
  • 김춘미 (이화여자대학교 약학대학)
  • Published : 2005.10.01

Abstract

DNA topoisomerase I(TOP1) helps the control of DNA replication, transcription and recombination by assist­ing breaking and rejoining of DNA double strand. Camptothecin (CPT) and its derivative, topotecan, are known to inhibit TOP1 by intercalating into TOP1-DNA complex. Recently various non-CPT intercalators are synthesized for a new class of TOP1 inhibitors. In this study, six compounds isolated from Poria cocos were investigated for their interaction with TOP1­DNA complex using the flexible docking program, FlexiDock. The binding modes were analyzed and compared with the TOP1 inhibition activities. The compounds that showed potent activity were intercalated between the + 1/-1 base pairs of DNA, located near the active site phosphotyrosine723 and formed hydrogen bonds with active site residues. On the other hand, compounds with no activity were not docked at all. The binding modes were well correlated with the inhibition activity, suggesting the possibility that potent inhibitors can be designed from the information presented by the docking study.

Keywords

References

  1. Chrencik, J. E., Staker, B. L., Burgin, A. B., Pourquier, P., Pommier, Y., Stewart, L. and Redinbo, M. R. : Mechanisms of camptothecin resistance by human topoisomerase I mutations. J. Mol. Biol. 339, 773 (2004) https://doi.org/10.1016/j.jmb.2004.03.077
  2. Staker, B. L., Hjerrild, K., Feese, M. D., Behnke, C. A., Burgin, A. B. Jr. and Stewart, L. : The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl. Acad. Sci. 99, 15387 (2002)
  3. Krogh, B. O. and Shuman, S. : Catalytic mechanism of DNA topoisomerase lB. Mol. Cell 5, 1035 (2000) https://doi.org/10.1016/S1097-2765(00)80268-3
  4. Liu, L. F., Desai, S. D., Li, T. K., Mao, Y., Sun, M. and Sim, S. P. : Mechanism of action of camptothecin. Ann. N. Y. Acad. Sci. 922, 1 (2000)
  5. Carey, J. F., Schultz, S. J., Sisson, L., Fazzio, T. G. and Champoux, J. J. : DNA relaxation by human topoisomerase I occurs in the closed clamp conformation of the protein. Proc. Natl. Acad. Sci. 100, 5640 (2003)
  6. Pommier, Y., Pourquier, P., Fan, Y. and Strumberg, D. : Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochim. Biophys. Acta. 1400, 83 (1998) https://doi.org/10.1016/S0167-4781(98)00129-8
  7. Kerrigan, J. E. and Pilch, D. S. : A structural model for the ternary cleavable complex formed between human topoisomerase I, DNA, and camptothecin. Biochemistry 40, 9792 (2001) https://doi.org/10.1021/bi010001j
  8. Laco, G. S., Du, W., Kohlhagen, G., Sayer, J. M., Jerina, D. M., Burke, T. G., Curran, D. P. and Pommier, Y. : Analysis of human topoisomerase I inhibition and interaction with the cleavage site +1 deoxyguanosine, via in vitro experiments and molecular modeling studies. Bioorg. Med. Chem. 12, 5225 (2004) https://doi.org/10.1016/j.bmc.2004.06.046
  9. Redinbo, M. R., Stewart, L., Kuhn, P., Champoux, J.J. and Hol, W. G. : Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science 279, 1504 (1998) https://doi.org/10.1126/science.279.5353.998
  10. Laco, G. S., Collins, J. R., Luke, B. T., Kroth, H., Sayer, J. M., Jerina, D. M. and Pommier, Y. : Human topoisomerase I inhibition: docking camptothecin and derivatives into a structure-based active site model. Biochemistry 41, 1428 (2002) https://doi.org/10.1021/bi011774a
  11. Fan, Y., Weinstein, J. N., Kohn, K. W., Shi, L. M. and Pommier, Y. : Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin. J. Med. Chem. 41, 2216 (1998) https://doi.org/10.1021/jm9605445
  12. Yamashita, Y., Fujii, N., Murakata, C., Ashizawa, T., Okabe, M. and Nakano, H. : Induction of mammalian DNA topoisomerase I mediated DNA cleavage by antitumor indolocarbazole derivatives. Biochemistry 31, 12069 (1992) https://doi.org/10.1021/bi00163a015
  13. Li, T. K., Bathory, E., LaVoie, E. J., Srinivasan, A. R., Olson, W. K., Sauers, R. R., Liu, L. F. and Pilch, D. S. : Human topoisomerase I poisoning by protoberberines: potential roles for both drug-DNA and drug-enzyme interactions. Biochemistry 39, 7107 (2000) https://doi.org/10.1021/bi000171g
  14. Jayaraman, M., Fox, B. M., Hollingshead, M., Kohlhagen, G., Pommier, Y. and Cushman, M. : Synthesis of new dihydroindeno[1,2-c]isoquinoline and indenoisoquinolinium chloride topoisomerase I inhibitors having high in vivo anticancer activity in the hollow fiber animal model. J. Med. Chem. 45, 242 (2002). https://doi.org/10.1021/jm000498f
  15. Capranico, G. and Binaschi, M. : DNA sequence selectivity of topoisomerases and topoisomerase poisons. Biochim. Biophys. Acta. 1400, 185 (1998) https://doi.org/10.1016/S0167-4781(98)00135-3
  16. Yamashita, Y, Kawada, S., Fujii, N. and Nakano, H. : Induction of mammalian DNA topoisomerase I and II mediated DNA cleavage by saintopin, a new antitumor agent from fungus. Biochemistry 30, 5838 (1991) https://doi.org/10.1021/bi00238a005
  17. Li, G., Xu, M. L., Lee, C. S., Woo, M. H., Chang, H. W. and Son, J. K. : Cytotoxicity and DNA topoisomerases inhibitory activity of constituents from the sclerotium of Poria cocos. Arch. Pharm. Res. 27, 829 (2004) https://doi.org/10.1007/BF02980174
  18. Ukiya, M., Akihisa, T., Tokuda, H., Hirano, M., Oshikubo, M., Nobukuni, Y, Kimura, Y., Tai, T., Kondo, S. and Nishino, H. : Inhibition of tumor-promoting effects by poricoic acids G and H and other lanostane-type triterpenes and cytotoxic activity of poricoic acids A and G from Poria cocos. J. Nat. Prod. 65, 462 (2002) https://doi.org/10.1021/np0103721
  19. Tai, T. S. T., Kikuchi, T., Tezka, Y and Akahori, A. : Triterpenes from the surface of Poria cocos. Phytochemistry 35, 1165-9 (1995)
  20. Giner-Larza, E. M., Manez, S., Giner-Pons, R. M., Carmen Recio, M. and Rios, J. L. : On the anti-inflammatory and anti-phospholipase A(2) activity of extracts from lanostane-rich species. J. Ethnopharmacol. 73, 61 (2000) https://doi.org/10.1016/S0378-8741(00)00276-2
  21. Yasukawa, K., Kaminaga, T., Kitanaka, S., Tai, T., Nunoura, Y., Natori, S. and Takido, M. : 3 beta-p-hydroxybenzoyldehydrotumulosic acid from Poria cocos, and its anti-inflammatory effect. Phytochemistry 48, 1357 (1998) https://doi.org/10.1016/S0031-9422(97)01063-7
  22. Mizushina, Y., Akihisa, T., Ukiya, M., Murakami, C., Kuriyama, I., Xu, X., Yoshida, H. and Sakaguchi, K. : A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane-type triterpene acids from Poria cocos. Cancer Sci. 95, 354 (2004) https://doi.org/10.1111/j.1349-7006.2004.tb03215.x
  23. Mizushina, Y., Tanaka, N., Kitamura, A., Tarnai, K., Ikeda, M., Takemura, M., Sugawara, E, Arai, T., Matsukage, A., Yoshida, S. and Sakaguchi, K. : The inhibitory effect of novel triterpenoid compounds, fomitellic acids, on DNA polymerase beta. Biochem. J. 330, 1325 (1998) https://doi.org/10.1042/bj3301325
  24. Tripos Co. Sybyl ver. 6.9.2. Manual (2004)
  25. Staker, B. L., Feese, M. D., Cushman, M., Pommier, Y., Zembower, D., Stewart, L. and Burgin, A. B. : Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J. Med. Chem. 48, 2336 (2005) https://doi.org/10.1021/jm049146p