Skip to main content

Advertisement

SpringerLink
Log in

Computational Studies and Drug Design for HIV-1 Reverse Transcriptase Inhibitors of 3′,4′-di-O-(S)-camphanoyl-(+)-cis-Khellactone (DCK) Analogs

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Summary

Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT. Based on the proposed mechanism, some new structures were designed and predicted by a SVM model. All compounds exhibited potent inhibitory activities against HIV replication in H9 lymphocytes with EC50 values lower than 1.95 μM. The rationality of the method was validated by experimental results.

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

Similar content being viewed by others

References

  1. A.L. Hopkins J.S. Ren R.M. Esnouf B.E. Willcox E.Y. Jones C. Ross T. Miyasaka R.T. Walker H. Tanaka D.K. Stammers D.I. Stuart (1996) J. Med. Chem. 39 1589 Occurrence Handle10.1021/jm960056x Occurrence Handle8648598

    Article  PubMed  Google Scholar 

  2. H. Mitsuya K.J. Weinhold P.A. Furman M.H. St. Clair L.S. Nusinoff R.C. D. Gallo Bolognesi D.W. Barry S. Broder (1985) Proc. Natl. Acad. Sci. USA 82 7096 Occurrence Handle2413459

    PubMed  Google Scholar 

  3. H. Mitsuya S. Broder (1986) Proc. Natl. Acad. Sci. USA 83 1911 Occurrence Handle3006077

    PubMed  Google Scholar 

  4. R. Yarchoan H. Mitsuya R.V. Thomas J.M. Pluda N.R. Hartman C.F. Perno K.S. Marczyk J.P. Allain D.G. Johns S. Broder (1989) Science 245 412 Occurrence Handle2502840

    PubMed  Google Scholar 

  5. J.A.V. Coates N. Cammack H.J. Jenkinson I.M. Mutton B.A. Pearson R. Storer J.M. Cameron C.R. Penn (1992) Antimicrob. Agents Chemother. 36 202 Occurrence Handle1590690

    PubMed  Google Scholar 

  6. E. Clercq ParticleDe (1993) Med. Res. Rev. 13 229 Occurrence Handle7683360

    PubMed  Google Scholar 

  7. L. Huang Y. Kashiwada L.M. Cosentino S. Fan K.H. Lee (1994) Bioorg. Med. Chem. Lett. 4 593 Occurrence Handle10.1016/S0960-894X(01)80161-X

    Article  Google Scholar 

  8. D.B. Kireev J.R. Chretien D.S. Grierson C. Monneret (1997) J. Med. Chem. 40 4257 Occurrence Handle10.1021/jm970110p Occurrence Handle9435895

    Article  PubMed  Google Scholar 

  9. M.J. HeravI F. Parastar (2000) J. Chem. Inf. Comput. Sci. 40 147 Occurrence Handle10.1021/ci990314+ Occurrence Handle10661561

    Article  PubMed  Google Scholar 

  10. R. Rizzo J.T. Rives W.L. Jorgenson (2001) J. Med. Chem. 44 145 Occurrence Handle10.1021/jm000255n Occurrence Handle11170624

    Article  PubMed  Google Scholar 

  11. M.A.L. Eriksson J. Pitera P.A. Kollman (1999) J. Med. Chem. 42 868 Occurrence Handle10.1021/jm980277y Occurrence Handle10072684

    Article  PubMed  Google Scholar 

  12. J. Huuskonen (2001) J. Chem. Inf. Comput. Sci. 41 425 Occurrence Handle10.1021/ci0001435 Occurrence Handle11277732

    Article  PubMed  Google Scholar 

  13. V., Vapnik (1998) Statistical Learning Theory Wiley New York

    Google Scholar 

  14. Cristianini, N. and Shawe-Taylor, J., An Introduction to Support Vector Machines. Cambridge University Press, Cambridge, UK, 2000

  15. Joachims, T., Learning to Classify Text Using Support Vector Machines: Methods, Theory, and Algorithms. Kluwer, 2002

  16. Schölkopf, B. and Smola, A., Learning with Kernels. MIT Press, Cambridge, MA, 2002

  17. Herbrich, R., Learning Kernel Classifiers. MIT Press, Cambridge, MA, 2002

  18. C.W. and Lin, C.J. Hsu (2002) IEEE Trans. Neural Networks. 13 415 Occurrence Handle10.1109/TNN.2002.1000139

    Article  Google Scholar 

  19. SYBYL. Tripos Associates Inc,Version 6.9, St. Louis, MO

  20. M. Clark III R.D. Cramer N. Opdenbosh ParticleVan (1989) J. Comput. Chem. 10 982 Occurrence Handle10.1002/jcc.540100804

    Article  Google Scholar 

  21. S.J.P. Weiner A. Kollman D.A. Case U.C. Singh C. Ghio G. Alagona S.J. Profeta P. Weiner (1984) J. Am. Chem. Soc. 106 765 Occurrence Handle10.1021/ja00315a051

    Article  Google Scholar 

  22. G.M. Morris D.S. Goodsell R.S. Halliday R. Huey W.E. Hart R.K. Belew A.J. Olson (1998) J. Comput. Chem. 19 1639 Occurrence Handle10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B

    Article  Google Scholar 

  23. G.M. Morris D.S. Goodsell R. Huey A.J. Olson (1996) J. Comput. – Aided Mol. Des. 10 293 Occurrence Handle10.1007/BF00124499 Occurrence Handle8877701

    Article  PubMed  Google Scholar 

  24. GROMACS, version 1.6; BIOSON Research Institute, Department of Biophysical Chemistry, University of Groningen, The Netherlands

  25. Berendsen H., van der Spoel D. and van Drunen R., (1995) Comput. Phys. Commun. 91 43

  26. D.T. Stanton P.C. Jurs (1990) Anal. Chem. 62 2323 Occurrence Handle10.1021/ac00220a013

    Article  Google Scholar 

  27. S. Clementi G. Cruciani P. Fifi D. Riganelli R. Valigi G. Musumarra (1995) Quant. Struct. – Act. Relat. 15 108

    Google Scholar 

  28. D. Eisenberg A.D. McLachlan (1986) Nature 319 199 Occurrence Handle10.1038/319199a0 Occurrence Handle3945310

    Article  PubMed  Google Scholar 

  29. A.C. Wallace R.A. Laskowski J.M. Thornton (1995) Protein Eng. 8 127 Occurrence Handle7630882

    PubMed  Google Scholar 

  30. H.F. Chen X.J. Yao Q. Li S.G. Yuan A. Panaye J.P. Doucet B.T. Fan (2003) SAR and QSAR Environ. Res. 14 455 Occurrence Handle10.1080/10629360310001624033

    Article  Google Scholar 

  31. V.N. Viswanadhan A.K. Ghose G.R. Revankar R.K. Robins (1989) J. Chem. Inf. Comput. Sci. 29 163 Occurrence Handle10.1021/ci00063a006

    Article  Google Scholar 

  32. C. Hansch A. Leo R.W. Taft (1991) Chem. Rev. 91 165 Occurrence Handle10.1021/cr00002a004

    Article  Google Scholar 

  33. E. Clercq ParticleDe (2002) Biochim. Biophys. Acta 1587 258 Occurrence Handle12084468

    PubMed  Google Scholar 

  34. L.T. Bacheler (1999) Drug Resist. Updates 2 56 Occurrence Handle10.1054/drup.1998.0064

    Article  Google Scholar 

  35. M. U. Blagović J. T. Rives W. L. Jorgensen (2004) J. Med. Chem. 47 2389 Occurrence Handle10.1021/jm0303507 Occurrence Handle15084137

    Article  PubMed  Google Scholar 

  36. H.F. Chen X.J. Yao M. Petitjean H.R. Xia J.H. Yao A. Panaye J.P. Doucet B.T. Fan (2004) QSAR Comb. Sci. 23 603 Occurrence Handle10.1002/qsar.200430884

    Article  Google Scholar 

  37. A. Macchiarulo L. Luca ParticleDe G. Costantino M.L. Barreca R. Gitto R. Pellicciari A. Chimirri (2004) J. Med. Chem. 47 1860 Occurrence Handle10.1021/jm0310838 Occurrence Handle15027880

    Article  PubMed  Google Scholar 

  38. H.F. Chen X.C. Dong B.S. Zeng K. Gao S.G. Yuan B.T. Fan C.Z. Zheng A. Panaye J.P. Doucet (2003) SAR and QSAR Environ. Res. 14 251 Occurrence Handle10.1080/1062936032000101493

    Article  Google Scholar 

  39. C.A. Lipinski F. Lombardo B.W. Dominy P.J. Feeney (1997) Adv. Drug Del. Rev. 23 3 Occurrence Handle10.1016/S0169-409X(96)00423-1

    Article  Google Scholar 

  40. Xie, L., Zhao, C.H., Zhou, T., Chen, H.F., Fan, B.T., Ma, J.Z., Li, J.Y., Bao, Z.Y., Lee, K.H., Allaway, G. and Lo, Z.W. Biorg. Med. Chem., (2005) in press

Download references

Author information

Author notes

  1. Hai-feng Chen

    Present address: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, 92697-3900, USA

Authors and Affiliations

  1. Department of Chemistry, University Paris 7-Denis Diderot, 1 rue Guy de la Brosse, 75005, Paris, France

    Hai-feng Chen, Bo-tao Fan & Chen-yang Zhao

  2. Beijing Institute of Pharmacology and Toxicology, 100850, Beijing, China

    Chun-hong Zhao & Ting Zhou

  3. Laboratory of Computer Chemistry, Shanghai Institute of Organic Chemistry, 200032, Shanghai, China

    Hai-feng Chen & Lan Xie

  4. School of Pharmacy, University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA

    Kuo-Hsiung Lee

  5. Panacos Pharmaceuticals Inc, 209 Perry Parkway, 20877, Gaithersburg, MD , USA

    Graham Allaway

Authors
  1. Hai-feng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo-tao Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chen-yang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lan Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chun-hong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ting Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kuo-Hsiung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Graham Allaway
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bo-tao Fan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, Hf., Fan, Bt., Zhao, Cy. et al. Computational Studies and Drug Design for HIV-1 Reverse Transcriptase Inhibitors of 3′,4′-di-O-(S)-camphanoyl-(+)-cis-Khellactone (DCK) Analogs. J Comput Aided Mol Des 19, 243–258 (2005). https://doi.org/10.1007/s10822-005-4790-2

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-005-4790-2

Keywords

Search

Navigation