Skip to main content
SpringerLink
Log in

Microscopic modes and free energies for topoisomerase I-DNA covalent complex binding with non-camptothecin inhibitors by molecular docking and dynamics simulations

  • Regular Article
  • Published:
Theoretical Chemistry Accounts Aims and scope Submit manuscript

Abstract

Topoisomerase I (Topo1) has been identified as an attractive target for anticancer drug development due to its central role in facilitating the nuclear process of the DNA. It is essential for rational design of novel Topo1 inhibitors to reliably predict the binding structures of the Topo1 inhibitors interacting with the Topo1-DNA complex. The detailed binding structures and binding free energies for the Topo1-DNA complex interacting with typical non-camptothecin Topo1 inhibitors have been examined by performing molecular docking, molecular dynamic simulations, and binding free energy calculations. The computational results provide valuable insights into the binding modes of the inhibitors binding with the Topo1-DNA complex and the key factors affecting the binding affinity. It has been demonstrated that the π–π stacking interaction with the DNA base pairs and the hydrogen bonding with Topo1 have the pivotal contributions to the binding structures and binding free energies, although the van der Waals and electrostatic interactions also significantly contribute to the stabilization of the binding structures. The calculated binding free energies are in good agreement with the available experiment activity data. The detailed binding modes and the crucial factors affecting the binding free energies obtained from the present computational studies may provide valuable insights for future rational design of novel, more potent Topo1 inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Scheme 2
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Xiao X, Antony S, Kohlhagen G, Pommier Y, Cushman M (2004) Bioorg Med Chem 12:5147

    Article  CAS  Google Scholar 

  2. Dancey J, Eisenhauer EA (1996) Br J Cancer 74:327

    Article  CAS  Google Scholar 

  3. Moisan F, Longy M, Robert J, Le Morvan V (2006) Br J Cancer 95:906

    Article  CAS  Google Scholar 

  4. Staker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin ABJ (2005) Med Chem 48:2336

    Article  CAS  Google Scholar 

  5. Xu CJ, Grainge I, Lee J, Harshey RM, Jayaram M (1998) Mol Cell 1:729

    Article  CAS  Google Scholar 

  6. Wasserman RA, Wang JCJ (1994) Biol Chem 269:20943

    CAS  Google Scholar 

  7. Wang JC (1996) Annu Rev Biochem 65:635

    Article  CAS  Google Scholar 

  8. Pommier Y (2009) Chem Rev 109:2894

    Article  CAS  Google Scholar 

  9. Staker BL (2002) Proc Natl Acad Sci 99:15387

    Article  CAS  Google Scholar 

  10. Wang JC (2002) Nat Rev Mol Cell Biol 3:430

    Article  CAS  Google Scholar 

  11. Teicher B (2008) Biochem Pharmacol 75:1262

    Article  CAS  Google Scholar 

  12. Cho W-J, Le QM, Van My HT, Youl Lee K, Kang BY, Lee E-S, Lee SK, Kwon Y (2007) Bioorg Med Chem Lett 17:3531

    Article  CAS  Google Scholar 

  13. Pommier Y, Pourquier P, Fan Y, Strumberg D (1998) Biochim Biophys Acta 1400:83

    Article  CAS  Google Scholar 

  14. Stewart L, Ireton GC, Champoux JJJ (1996) Biol Chem 271:7602

    Article  CAS  Google Scholar 

  15. Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WGJ (1998) Science 279:1504

    Article  CAS  Google Scholar 

  16. Stewart L, Redinbo MR, Qiu XY, Hol WGJ, Champoux JJ (1998) Science 279:1534

    Article  CAS  Google Scholar 

  17. Gohlke H, Klebe G (2002) Angewandte Chemie-International Ed 41:2645

    Google Scholar 

  18. Lima CD, Wang JC, Mondragon A (1994) Nature 367:138

    Article  CAS  Google Scholar 

  19. Yu LP, Zhu CX, Tsedinh YC, Fesik SW (1995) Biochemistry 34:7622

    Article  CAS  Google Scholar 

  20. Wall ME, Wani MC, Cook CE, Palmer KH, Mcphail AT, Sim GA (1966) J Am Chem Soc 88:3888

    Article  CAS  Google Scholar 

  21. Hsiang YH, Hertzberg R, Hecht S, Liu LFJ (1985) Biol. Chem. 260:14873

    CAS  Google Scholar 

  22. Nitiss J, Wang JC (1988) Proc. Natl. Acad. Sci. U. S. A. 85:7501

    Article  CAS  Google Scholar 

  23. Hertzberg RP, Caranfa MJ, Hecht SM (1989) Biochemistry 28:4629

    Article  CAS  Google Scholar 

  24. Chen AY, Liu LF (1994) Annu Rev Pharmacol Toxicol 34:191

    Article  CAS  Google Scholar 

  25. Hashimoto K, Man S, Xu P, Cruz-Munoz W, Tang T, Kumar R, Kerbel RS (2010) Mol Cancer Ther 9:996

    Article  CAS  Google Scholar 

  26. Tsunetoh S, Terai Y, Sasaki H, Tanabe A, Tanaka Y, Sekijima T, Fujiwara S, Kawaguchi H, Kanemura M, Yamashita Y, Ohmichi M (2010) Cancer Biol Ther 10:1138

    Google Scholar 

  27. Armand JP, Ducreux M, Mahjoubi M, Abigerges D, Bugat R, Chabot G, Herait P, de Forni M, Rougier P (1995) Eur J Cancer 31A:1283

    Article  CAS  Google Scholar 

  28. O’Reilly S, Rowinsky EK (1996) Crit Rev Oncol Hematol 24:47

    Article  Google Scholar 

  29. Taniguchi K, Kohno K, Kawanami K, Wada M, Kanematsu T, Kuwano M (1996) Cancer Res 56:2348

    CAS  Google Scholar 

  30. Soret J, Gabut M, Dupon C, Kohlhagen G, Stevenin J, Pommier Y, Tazi J (2003) Cancer Res 63:8203

    CAS  Google Scholar 

  31. Liao Z, Robey RW, Guirouilh-Barbat J, Kenneth KW, Polgar O, Bates SE, Pommier Y (2008) Mol Pharmacol 73:490

    Article  CAS  Google Scholar 

  32. Rasheed ZA, Rubin EH (2003) Oncogene 22:7296

    Article  CAS  Google Scholar 

  33. Urasaki Y, Laco G, Takebayashi Y, Bailly C, Kohlhagen G, Pommier Y (2001) Cancer Res 61:504

    CAS  Google Scholar 

  34. Kohlhagen G, Paull KD, Cushman M, Nagafuji P, Pommier Y (1998) Mol Pharmacol 54:50

    CAS  Google Scholar 

  35. Pommier YG, Antony S, Agama K, Miao ZH, Takagi K, Bates S, Wright MH, Robbles AI, Varticovski L, Nagarajan M, Morre A, Cushman M (2007) Mol Cancer Ther 6:3598s

    Google Scholar 

  36. Kiselev E, Dexheimer TS, Pommier Y, Cushman MJ (2010) Med Chem 53:8716

    Article  CAS  Google Scholar 

  37. Khadka DB, Cho WJ (2011) Bioorg Med Chem 19:724

    Article  CAS  Google Scholar 

  38. Ruchelman AL, Singh SK, Ray A, Wu XH, Yang JM, Li TK, Liu A, Liu LF, LaVoie EJ (2003) Bioorg Med Chem 11:2061

    Article  CAS  Google Scholar 

  39. Ruchelman AL, Singh SK, Wu X, Ray A, Yang JM, Li TK, Liu A, Liu LF, LaVoie EJ (2002) Bioorg Med Chem Lett 12:3333

    Article  CAS  Google Scholar 

  40. Li TK, Houghton PJ, Desai SD, Daroui P, Liu AA, Hars ES, Ruchelman AL, LaVoie EJ, Liu LF (2003) Cancer Res 63:8400

    CAS  Google Scholar 

  41. Kurtzberg LS, Roth S, Krumbholz R, Crawford J, Bormann C, Dunham S, Yao M, Rouleau C, Bagley RG, Yu XJ, Wang F, Schmid SM, LaVoie EJ, Teicher BA (2011) Clin Cancer Res 17:2777

    Article  CAS  Google Scholar 

  42. Ruchelman AL, Singh SK, Wu XH, Ray A, Yang JM, Li TK, Liu A, Liu LF, LaVoie EJ (2002) Bioorg Med Chem Lett 12:3333

    Article  CAS  Google Scholar 

  43. Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman MJ (2005) Med Chem 48:4803

    Article  CAS  Google Scholar 

  44. Omega-2.2. www.eyesopen.com (2007)

  45. Bostrom J (2001) J Comput-Aided Mol Des 15:1137

    Google Scholar 

  46. Bostrom J, Greenwood JR, Gottfries JJ (2003) Mol. Graphics Modell. 21:449

    Article  CAS  Google Scholar 

  47. Fred V. www.eyesopen.com (2007)

  48. McGann MR, Almond HR, Nicholls A, Grant JA, Brown FK (2003) Biopolymers 68:76

    Article  CAS  Google Scholar 

  49. Gatchell DW, Dennis S, Vajda S (2000) Prot Struct Func Genet 41:518

    Article  CAS  Google Scholar 

  50. Kozakov D, Clodfelter KH, Vajda S, Camacho CJ (2005) Biophys J 89:867

    Article  CAS  Google Scholar 

  51. Hamza A, Zhan CGJ (2009) Phys. Chem. B 113:2896

    CAS  Google Scholar 

  52. Li Q-Y, Zu Y-G, Shi R-Z, Yao L-P (2006) Curr Med Chem 13:2021

    Article  CAS  Google Scholar 

  53. Eldridge MD, Murray CW, Auton TR, Paolini GV, Mee RP (1997) J. Comput Aided Mol Des 11:425

    Google Scholar 

  54. Gehlhaar DK, Verkhivker GM, Rejto PA, Sherman CJ, Fogel DB, Fogel LJ, Freer ST (1995) Chem Biol 2:317

    Article  CAS  Google Scholar 

  55. Stahl M, Rarey MJ (1035) Med Chem 2001:44

    Google Scholar 

  56. Case DA, Darden TA, Cheatham TE I, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts B, Wang B, Hayik S, Roitberg A, Seabra G, Kolossváry I, Wong KF, Paesani F, Vanicek J, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh M-J, Cui G, Roe DR, Mathews DH, Seetin MG, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2010) University of California, San Francisco

  57. Hamza A, AbdulHameed MDM, Zhan CGJ (2008) Phys. Chem. B 112:7320

    Article  CAS  Google Scholar 

  58. Hamza A, Tong M, AbdulHameed MD, Liu J, Goren AC, Tai HH, Zhan CG (2010) J Phys Chem B. 114:5605

    Article  CAS  Google Scholar 

  59. Hamza A, Zhan CGJ (2006) Phys. Chem. B 110:2910

    Article  CAS  Google Scholar 

  60. Zhan CG, Yang B, Hamza A, Chen GJ, Wang YJ (2010) Phys. Chem. B 114:16020

    Article  Google Scholar 

  61. Wang JM, Wolf RM, Caldwell JW, Kollman PA, Case DAJ (2004) Comput Chem 25:1157

    Article  CAS  Google Scholar 

  62. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong GM, Zhang W, Yang R, Cieplak P, Luo R, Lee T, Caldwell J, Wang JM, Kollman PJ (1999) Comput Chem 2003:24

    Google Scholar 

  63. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Zakrzewski VG, Montgomery JA, Stratmann RE, Burant JC, Dapprich S, Millan JM, Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Malich DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Baboul AG, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Gonzales C, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Andreas JL, Head-Gordon M, Reploge ES, Pople JA (2003) Gaussian03, Gaussian, Inc.: Pittsburgh

  64. Cieplak P, Cornell WD, Bayly C, Kollman PAJ (1995) Comput Chem 16:1357

    Article  CAS  Google Scholar 

  65. Bayly CI, Cieplak P, Cornell WD, Kollman PAJ (1993) Phys. Chem. 97:10269

    Article  CAS  Google Scholar 

  66. Jorgensen WLJ (1981) Am. Chem. Soc. 103:335

    Article  CAS  Google Scholar 

  67. Berendsen HJC, Postma JPM, Vangunsteren WF, Dinola A, Haak JRJ (1984) Chem Phys 81:3684

    CAS  Google Scholar 

  68. Ryckaert JP, Ciccotti G, Berendsen HJCJ (1977) Comput. Phys. 23:327

    Article  CAS  Google Scholar 

  69. Darden T, York D, Pedersen LJ (1993) Chem Phys 98:10089

    CAS  Google Scholar 

  70. Kollman PA, Massova I, Reyes C, Kuhn B, Huo SH, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE (2000) Acc Chem Res 33:889

    Article  CAS  Google Scholar 

  71. Moreira IS, Fernandes PA, Ramos MJ (2006) J Phys Chem B 110:10962

    Article  CAS  Google Scholar 

  72. Zhao YH, Abraham MH, Zissimos AMJ (2003) Org. Chem. 68:7368

    Article  CAS  Google Scholar 

  73. Hawkins GD, Cramer CJ, Truhlar DGJ (1996) Phys. Chem. 100:19824

    Article  CAS  Google Scholar 

  74. Hawkins GD, Cramer CJ, Truhlar DG (1995) Chem Phys Lett 246:122

    Article  CAS  Google Scholar 

  75. Harvey SC (1989) Prot Struct Funct Genet 5:78

    Article  CAS  Google Scholar 

  76. Dong GQ, Sheng CQ, Wang SZ, Miao ZY, Yao JZ, Zhang WNJ (2010) Med Chem 53:7521

    Article  CAS  Google Scholar 

  77. Kurtzberg LS, Battle T, Rouleau C, Bagley RG, Agata N, Yao M, Schmid S, Roth S, Crawford J, Krumbholz R, Ewesuedo R, Yu XJ, Wang F, Lavoie EJ, Teicher BA (2008) Mol Cancer Ther 7:3212

    Article  CAS  Google Scholar 

  78. Khadka DB, Cho W-J (2011) Bioorg Med Chem 19:724

    Article  CAS  Google Scholar 

  79. Yang B, Hamza A, Chen G, Wang Y, Zhan CGJ (2010) Phys. Chem. B 114:16020

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the NIH (grant RC1 MH088480 to Zhan) and the NSF (grant CHE-1111761 to Zhan). Wei worked in Dr. Zhan’s laboratory for this project as an exchange student from Dalian University of Technology. The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell X-series Cluster with 384 nodes or 4,768 processors. Wei also appreciates the scholarship from Chinese Scholarship Council (CSC).

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA

    Ning-Ning Wei, Adel Hamza & Chang-Guo Zhan

  2. State Key Laboratory of Fine Chemicals, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 116024, China

    Ning-Ning Wei, Ce Hao & Zhilong Xiu

Authors
  1. Ning-Ning Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adel Hamza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ce Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhilong Xiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chang-Guo Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chang-Guo Zhan.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 651 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wei, NN., Hamza, A., Hao, C. et al. Microscopic modes and free energies for topoisomerase I-DNA covalent complex binding with non-camptothecin inhibitors by molecular docking and dynamics simulations. Theor Chem Acc 132, 1379 (2013). https://doi.org/10.1007/s00214-013-1379-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00214-013-1379-z

Keywords

Search

Navigation