YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Docking Studies of Camptothecin Analogues into Human Topoisomerase I-DNA Complex

Camptothecin 유도체의 Human Topoisomerase I-DNA 복합체에 대한 Docking 연구

  • Park, In-Seon (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Kim, Bo-Yeon (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Kim, Choon-Mi (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Choi, Sun (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University)
  • 박인선 (이화여자대학교 약학대학 대학원 생명.약학부) ;
  • 김보연 (이화여자대학교 약학대학 대학원 생명.약학부) ;
  • 김춘미 (이화여자대학교 약학대학 대학원 생명.약학부) ;
  • 최선 (이화여자대학교 약학대학 대학원 생명.약학부)
  • Published : 2009.08.31
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Abstract

Human topoisomerase I (Topo I) plays a pivotal role in cell replication, transcription and repair and, therefore, is an important anti-cancer target. 20S-camptothecin (CPT) is a representative Topo I inhibitor. Compounds belonging to CPT family inhibit the religation step of Topo I-DNA by binding to the DNA cleavage site. Computational docking studies with Surflex-Dock were carried out to investigate the binding modes between Topo I-DNA binary complex structure and the ligand such as 20S-CPT and 9,10-substituted 20S-CPT analogues. The docking results demonstrated that most of the compounds with $IC_{50}$ value under $0.5{\mu}M$ intercalated exactly between the -1 and +1 DNA bases, deeply toward the cleavage site. The complex was stabilized by hydrogen-bonding and hydrophobic interactions with both the enzyme and the DNA. The compounds with $IC_{50}$ value above $0.5{\mu}M$ were poorly docked and did not intercalate. In addition, the docking results confirmed the overall correlation between the $IC_{50}$ values and docking scores, indicating the possible use of the modeling for the prediction of biological activity and design of potential inhibitors.

Keywords

References

  1. Wang, J. C. : DNA topoisomerases. Annual Review of Biochemistry 65, 635 (1996) https://doi.org/10.1146/annurev.bi.65.070196.003223
  2. Stewart, L., Redinbo, M. R., Qiu, X., Hol, W. G. and Champoux, J. J. : A model for the mechanism of human topoisomerase I. Science (New York, N.Y) 279, 1534 (1998) https://doi.org/10.1126/science.279.5356.1534
  3. 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
  4. Champoux, J. J. : DNA topoisomerases: structure, function, and mechanism. Annual Review of Biochemistry 70, 369 (2001) https://doi.org/10.1146/annurev.biochem.70.1.369
  5. Pourquier, P., Pilon, A. A., Kohlhagen, G., Mazumder, A., Sharma, A. and Pommier, Y. : Trapping of mammalian topoisomerase I and recombinations induced by damaged DNA containing nicks or gaps. Importance of DNA end phosphorylation and camptothecin effects. The Journal of Biological Chemistry 272, 26441 (1997) https://doi.org/10.1074/jbc.272.42.26441
  6. Pourquier, P., Ueng, L. M., Kohlhagen, G., Mazumder, A., Gupta, M., Kohn, K. W. and Pommier, Y. : Effects of uracil incorporation, DNA mismatches, and abasic sites on cleavage and religation activities of mammalian topoisomerase I. The Journal of Biological Chemistry 272, 7792 (1997) https://doi.org/10.1074/jbc.272.12.7792
  7. Lesher, D. T. T., Pommier, Y., Stewart, L. and Redinbo, M. R. : 8- Oxoguanine rearranges the active site of human topoisomerase I. Proc. Natl. Acad. Sci. U.S.A. 99, 12102 (2002) https://doi.org/10.1073/pnas.192282699
  8. Chreneik, J. E., Burgin, A. B., Pommier, Y., Stewart, L. and Redinbo, M. R. : Structural impact of the leukemia drug 1-beta-D-arabinofuranosyleytosine (Ara-C) on the covalent human topoisomerase I-DNA complex. J. Biol. Chem. 278, 12461 (2003) https://doi.org/10.1074/jbc.M212930200
  9. Meng, L. H., Liao, Z. Y. and Pommier, Y. : Non-camptothecin DNA topoisomerase I inhibitors in cancer therapy. Current Topics in Medicinal Chemistry 3, 305 (2003) https://doi.org/10.2174/1568026033452546
  10. Pizzolato, J. F. and Saltz, L. B. : The camptothecins. Lancet 361, 2235 (2003) https://doi.org/10.1016/S0140-6736(03)13780-4
  11. Wall, M. E. and Wani, M. C. : Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture. Cancer Research 55, 753 (1995)
  12. Li, T. K. and Liu, L. F. : Tumor cell death induced by topoisomerase-targeting drugs. Annual Review of Pharmacology and Toxicology 41, 53 (2001) https://doi.org/10.1146/annurev.pharmtox.41.1.53
  13. Sordet, O., Khan, Q. A., Kohn, K. W. and Pommier, Y. : Apoptosis induced by topoisomerase inhibitors. Current Medicinal Chemistry 3, 271 (2003)
  14. Redinbo, M. R., Champoux, J. J. and Hol, W. G. J. : Novel insights into catalytic mechanism from a crystal structure of human topoisomerase I in complex with DNA. Biochemistry 39, 6832 (2000) https://doi.org/10.1021/bi992690t
  15. Pommier, Y., Pourquier, P., Fan, Y. and Strumberg, D. : Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochimica et Biophysica Acta 1400, 83 (1998) https://doi.org/10.1016/S0167-4781(98)00129-8
  16. 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
  17. 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/bi010913l
  18. 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. Proceedings of the National Academy of Sciences of the United States of America 99, 15387 (2002) https://doi.org/10.1073/pnas.242259599
  19. 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. Bioorganic & Medicinal Chemistry 12, 5225 (2004) https://doi.org/10.1016/j.bmc.2004.06.046
  20. Redinbo, M. R., Stewart, L., Kuhn, P., Champoux, J. J. and Hol, W. G. J. : Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science 279, 1504 (1998) https://doi.org/10.1126/science.279.5356.1504
  21. 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
  22. Thomas, C. J., Rahier, N. J. and Hecht, S. M. : Camptothecin: current perspectives. Bioorganic & Medicinal Chemistry 12, 1585 (2004) https://doi.org/10.1016/j.bmc.2003.11.036
  23. 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
  24. Krogh, B. O. and Shuman, S. : Catalytic mechanism of DNA topoisomerase IB. Mol. Cell 5, 1035 (2000) https://doi.org/10.1016/S1097-2765(00)80268-3
  25. Jain, A. N. : Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J. Me.d Chem. 46, 499 (2003) https://doi.org/10.1021/jm020406h
  26. Jain, A. N. : Surflex-Dock 2.1: Robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search. J. Comput. Aided Mol. Des. 21, 281 (2007) https://doi.org/10.1007/s10822-007-9114-2
  27. Jones, G., Willett, P., Glen, R. C., Leach, A. R. and Taylor, R. : Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol. 267, 727 (1997) https://doi.org/10.1006/jmbi.1996.0897
  28. Wall, M. E., Wani, M. C., Nicholas, A. W., Manikumar, G., Tele, C., Moore, L., Truesdale, A., Leitner, P. and Besterman, J. M. : Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs. J. Med. Chem. 36, 2689 (1993) https://doi.org/10.1021/jm00070a013