Skip to main content

Molecular Dynamics Simulation Approach to Understand Lamivudine Resistance in Hepatitis B Virus Polymerase

Hepatitis B virus (HBV) is a global threat that killed many human lives. HBV DNA polymerase (HDP) is the key target for antiviral drug treatment. The widely used drug against HBV infection is lamivudine which targets the reverse transcriptase activity of HDP and inhibits the replication of HBV. However, available evidence demonstrated that tyrosine (Y)-methionine (M)-aspartic acid (D)-aspartic acid (D) motif mutations significantly affected the efficacy of lamivudine binding. In particular, M204I mutations affect the drug binding mechanism and cause resistance to lamivudine. Therefore, in the present study we made an attempt to understand the mechanism of lamivudine resistance with the aid of molecular docking and molecular dynamics (MD) approach. The molecular docking results suggest that lamivudine adopts the most promising conformations to the native type HDP by identifying M-204 and Y-203 as a prospective partner for making polar contacts as compared to the mutant type HDP. The MD results showed that the average movements of atoms, especially atoms of the native type HDP– lamivudine complex, were small and displayed fast convergence of energy and charges in geometry. This highlights the stable binding of lamivudine with native type HDP as compared to mutant type HDP. The R2 and RMSF analysis certainly indicates conformational changes in the HDP structure due to M204I mutation. Furthermore the hydrogen bond (H-bond) analysis from the MD study showed that there is decreased number of intermolecular H-bonds in mutant HDP – lamivudine complex as compared to that in native type HDP – lamivudine complex. Overall, our study certainly will pave way to develop new drugs against the drug resistant mutations (M204I) of HBV.

This is a preview of subscription content, access via your institution.

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

References

  1. 1.

    T. J. Liang, Hepatology, 49, 13 – 21 (2009).

    Article  Google Scholar 

  2. 2.

    D. Lavanchy, J. Clin. Virol., 34, 1 – 3 (2005).

    Google Scholar 

  3. 3.

    S. A. Wynne, R. A. Crowther, and A. G. Leslie, Mol. Cell, 6, 771 – 780 (1999).

    Article  Google Scholar 

  4. 4.

    B. J. McMahon, Hepatol. Intern., 3, 334 – 342 (2009)

    Article  Google Scholar 

  5. 5.

    C. Mayerat, A. Mantegani, and P. C. Frei, J. Viral Hepatol., 6, 299 – 304 (1999).

    CAS  Article  Google Scholar 

  6. 6.

    K.-H. Kim, N. D. Kim, and B.-L. Seong, Molecules, 15(9), 5878 – 5908 (2010).

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    M. Seifer and D. N. Standring, J. Virol., 67, 4513 – 4520 (1993).

    PubMed Central  CAS  PubMed  Google Scholar 

  8. 8.

    L. Lin and J. Hu, J. Virol., 82(5), 2305 – 2312 (2008).

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  9. 9.

    F. Zoulim, Liver Intern., 1, 111 – 116 (2011).

    Article  Google Scholar 

  10. 10.

    M. Seifer, A. Patty, I. Serra, et al., Antivir. Res., 81(2), 147 – 155 (2009).

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    T. T. Chang, R. G. Gish, R. de Man, et al., New Engl. J. Med., 354(10), 1001 – 10 (2006).

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    B. Dikici, M. Bosnak, I. H. Kara, et al., Pediatr. Infect. Dis. J., 20(10), 988 – 992 (2001).

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    M. F. Yuen and C. L. Lai, J. Antimicrob. Chemother., 51(3), 481 – 485 (2003).

    CAS  Google Scholar 

  14. 14.

    R. K. Gaillard, J. Barnard, V. Lopez, et al., Antimicrob. Agents Chemother., 46 (4), 1005 – 1013 (2002).

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  15. 15.

    T. Schwede, J. Kopp, N. Guex, and M. C. Peitsch, Nucl. Acid Res., 31(13), 3381 – 3385 (2003).

    CAS  Article  Google Scholar 

  16. 16.

    N. Guex and M. C. Peitsch, Electrophoresis, 18(15), 2714 – 2723 (1997).

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    B. Hess, C. Kutzner, D. Spoel, and E. Lindahl, J. Chem. Theory Comput., 4, 435 – 447 (2008).

    CAS  Article  Google Scholar 

  18. 18.

    D. Spoel, E. Lindahl, B. Hess, et al., J. Comput. Chem., 26(16), 1701 – 1718 (2005).

    Article  Google Scholar 

  19. 19.

    J. Feldman, K. A. Snyder, A. Ticoll, et al., FEBS Lett., 580, 1649 – 1653 (2006).

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    J. Gasteiger, C. Rudolph and J. Sadowski, Tetrahedron Comput Meth., 3, 537 – 547. (1990).

    CAS  Article  Google Scholar 

  21. 21.

    P. R. Daga, J. Duan, and R. J. Doerksen, Protein Sci., 19, 796 – 807 (2010).

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  22. 22.

    A. M. Ismail, O. P. Sharma, M. S. Kumar, et al., Bioinformation, 9, 121 – 125 (2013).

    PubMed Central  Article  PubMed  Google Scholar 

  23. 23.

    A. W. Walsh, D. R. Langley, R. J. Colonno, et al., PLoS One, 5, e9195 (2010).

    PubMed Central  Article  PubMed  Google Scholar 

  24. 24.

    R. A. Laskowski, M. W. MacArthur, D. S. Moss, and J. M. Thornton, J. Appl. Cryst., 26(2), 283 – 2911 (1993).

    CAS  Article  Google Scholar 

  25. 25.

    Z. Yuan, T. L. Bailey, and R. D. Teasdale, Proteins, 58, 905 – 912 (2005).

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    D. Ringe and G. A. Petsko, Methods Enzymol., 131, 389 – 433 (1986).

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    S. Parthasarathy and M. R. Murthy, Protein Eng., 13, 9 – 13 (2000).

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    H. A. Carlson and J. A. McCammon, Mol. Pharmacol., 57, 213 – 218 (2000).

    CAS  PubMed  Google Scholar 

  29. 29.

    V. Karthick, V. Shanthi, R. Rajasekaran and K. Ramanathan, Protoplasma, 250(1), 197 – 207 (2013).

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    R. Rajasekaran, C. George Priya Doss, C. Sudandiradoss, et al., C. R. Biol., 331, 409 – 417 (2008).

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    A. Hinkle and L. S. Tobacman, J. Biol. Chem., 278, 506 – 513 (2003).

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    K. Suhre and Y. H. Sanejouand, Nucl. Acids Res., 32, 610 – 614 (2004).

    Article  Google Scholar 

  33. 33.

    A. Oda, M. Okayasu, Y. Kamiyama, et al., Bull. Chem. Soc. Jpn., 80, 1920 – 1925 (2007).

    CAS  Article  Google Scholar 

  34. 34.

    A. C. Wallace, R. A. Laskowski, and J. M. Thornton, Protein Eng., 8, 127 – 134 (1995).

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    K. L. Meagher and H. A. Carlson, Proteins, 58, 119 – 125 (2005).

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    A. W. Schuttelkopf and D. M. F. Van Aalten, Acta Crystallogr., 60, 1355 – 1363 (2004).

    Google Scholar 

  37. 37.

    T. Darden, L. Perera and L. Pedersen, Structure, 7, 55 – 60 (1999).

    Article  Google Scholar 

  38. 38.

    E. Hindahl, B. Hess and D. van der Spoel, J. Mol. Model., 7, 306 – 317 (2001).

    Google Scholar 

  39. 39.

    R. T. Kroemer, Curr. Protein Pept. Sci., 8, 312 – 328 (2007)

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    J. Fung, C. L. Lai, W. K. Seto, and M. F. Yuen, J. Antimicrob Chemother., 66, 2715 – 2725 (2011).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors express deep gratitude to management of the Vellore Institute of Technology for all the support, assistance, and constant encouragement to carry out this work

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to K. Ramanathan.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Srividhya, M., Ramanathan, K. Molecular Dynamics Simulation Approach to Understand Lamivudine Resistance in Hepatitis B Virus Polymerase. Pharm Chem J 49, 432–438 (2015). https://doi.org/10.1007/s11094-015-1300-2

Download citation

Keywords

  • HBV DNA polymerase
  • drug resistance
  • molecular docking
  • molecular dynamics simulation