Skip to main content

Advertisement

SpringerLink
Log in

Understanding the structure-activity relationship of betulinic acid derivatives as anti-HIV-1 agents by using 3D-QSAR and docking

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Novel anti-HIV-1 agents derived from betulinic acid have been greatly concerned. 3D-QSAR and molecular docking studies were applied to rationalize the structural requirements responsible for the anti-HIV activity of these compounds. The CoMFA and CoMSIA models resulted from 28 molecules gave r 2cv values of 0.599 and 0.630, r 2 values of 0.994 and 0.958, respectively. To estimate the predictive ability of the 3D-QSAR model, an external validation was employed. Based on the contour maps generated from both CoMFA and CoMSIA, we have identified some key features in the betulinic acid derivatives that are responsible for the anti-HIV activity. Molecular docking was used to explore the binding mode between these derivatives and HIV gp120. We have therefore designed a series of novel betulinic acid derivatives by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provide a valuable method to design new betulinic acid derivatives as anti-HIV-1 agents.

3D-QSAR and molecular docking studies were applied to rationalize the structural requirements responsible for the anti-HIV activity of betulinic acid derivatives.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

References

  1. Sun IC, Wang HK, Kashiwada Y, Shen JK, Cosentino LM, Chen CH, Yang LM, Lee KH (1998) Anti-AIDS Agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents. J Med Chem 41:4648–4657

    Article  CAS  Google Scholar 

  2. Hashimoto F, Kashiwada Y, Cosentino LM, Chen CH, Garrett PE, Lee KH (1997) Anti-AIDS Agents-XXVII. Synthesis and anti-HIV activity of beulinic acid and dihydrobetulinic acid derivatives. Bioorg Med Chem 12:2133–2143

    Article  Google Scholar 

  3. Gerrish D, Kim IC, Kumar DV, Austin H, Garrus JE, Baichwal V, Saunders M, Mckinnon RS, Anderson MB, Carlson R, Arranz-Plaza E, Yager KM (2008) Triterpene based compounds with potent anti-maturation activity against HIV-1. Bioorg Med Chem Lett 18:6377–6380

    Article  CAS  Google Scholar 

  4. Evers M, Poujade C, Soler F, Ribeill Y, James C, Lelievre Y, Gueguen JC, Reisdorf D, Morize I, Pauwels R, Clercq ED, Henin Y, Bousseau A, Mayaux JF, Pecq JBL, Dereu N (1996) Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action. J Med Chem 39:1056–1068

    Article  CAS  Google Scholar 

  5. Huang L, Ho P, Lee KH, Chen CH (2006) Synthesis and anti-HIV activity of bi-functional betulinic acid derivatives. Bioorg Med Chem 14:2279–2289

    Article  CAS  Google Scholar 

  6. Dang Z, Lai W, Qian K, Ho P, Lee KH, Chen CH, Huang L (2009) Betulinic acid derivatives as human immunodeficiency virus type 2 (HIV-2) inhibitors. J Med Chem 52:7887–7891

    Article  CAS  Google Scholar 

  7. Soler F, Poujade C, Evers M, Carry JC, Henin Y, Bousseau A, Huet T, Pauwels R, Clercq ED, Mayaux JF, Pecq JBL, Dereu N (1996) Betulinic acid derivatives: a new class of specific inhibitors of human immunodeficiency virus type 1 entry. J Med Chem 39:1069–1083

    Article  CAS  Google Scholar 

  8. Qian K, Yu D, Chen CH, Huang L, Morris-Natschke SL, Nitz TJ, Salzwedel K, Reddick M, Allaway GP, Lee KH (2009) Anti-AIDS Agents. 78. design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents. J Med Chem 52:3248–3258

    Article  CAS  Google Scholar 

  9. Pohjala L, Alakurtti S, Ahola T, Yli-Kauhaluoma J, Tammela P (2009) Betulin-derived compounds as inhibitors of alphavirus replication. J Nat Prod 72:1917–1926

    Article  CAS  Google Scholar 

  10. Sybyl 8.1, Tripos Inc, St. Louis, US

  11. Song QL, Sun PH, Chen WM (2010) Exploring 3D-QSAR for ketolide derivatives as antibacterial agents using CoMFA and CoMSIA. Lett Drug Des Discov 7:149–159

    Article  CAS  Google Scholar 

  12. Lan P, Huang ZJ, Sun JR, Chen WM (2010) 3D-QSAR and molecular docking studies on fused pyrazoles as p38α mitogen-activated protein kinase inhibitors. Int J Mol Sci 11:3357–3374

    Article  CAS  Google Scholar 

  13. Cichero E, Cesarini S, Fossa P, Spallarossa A, Mosti L (2009) Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors: docking-based CoMFA and CoMSIA analyses. Eur J Med Chem 44:2059–2070

    Article  CAS  Google Scholar 

  14. Puntambekar DS, Giridhar R, Yadav MR (2006) Understanding the antitumor activity of novel tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors using CoMFA and CoMSIA. Eur J Med Chem 41:1279–1292

    Article  CAS  Google Scholar 

  15. Cichero E, Cesarini S, Mosti L, Fossa P (2010) CoMFA and CoMSIA analyses on 4-oxo-1, 4-dihydroquinoline and 4-oxo-1, 4-dihydro-1, 5-, -1, 6- and -1, 8-naphthyridine derivatives as selective CB2 receptor agonists. J Mol Model 16:677–691

    Article  CAS  Google Scholar 

  16. Murugesan V, Prabhakar YS, Katti SB (2009) CoMFA and CoMSIA studies on thiazolidin-4-one as anti-HIV-a agents. J Mol Graph Model 27:735–743

    Article  CAS  Google Scholar 

  17. Choo HYP, Choi S, Jung SH, Koh HY, Pae AN (2003) The 3D-QSAR study of antitumor arylsulfonylimidazolidinone derivatives by CoMFA and CoMSIA. Bioorg Med Chem 11:4585–4589

    Article  Google Scholar 

  18. Choo HYP, Lim JS, Kam Y, Kim SY, Lee J (2001) A comparative study of quantitative structure activity relationship methods based on antitumor diarylsulfonylureas. Eur J Med Chem 36:829–836

    Article  Google Scholar 

  19. Tsukada T, Takahashi M, Takemoto T, Kanno O, Yamane T, Kawamura S, Nishi T (2010) Structure-based drug design of tricyclic 8H-indeno[1, 2-d][1, 3]thiazoles as potent FBPase inhibitors. Bioorg Med Chem Lett 20:1004–1007

    Article  CAS  Google Scholar 

  20. Golbraikh A, Tropsha A (2002) Beware of q2. J Mol Graph Model 20:269–276

    Article  CAS  Google Scholar 

  21. Roy PP, Roy K (2008) On some aspects of variable selection for partial least squares regression models. QSAR Comb Sci 27:302–313

    Article  CAS  Google Scholar 

  22. Lu P, Wei X, Zhang R (2010) CoMFA and CoMSIA 3D-QSAR studies on quionolone carboxylic acid derivatives inhibitors of HIV-1 integrase. Eur J Med Chem 45:3413–3419

    Article  CAS  Google Scholar 

  23. Basu A, Jasu K, Jayaprakash V, Mishra N, Ojha P, Bhattacharya S (2009) Development of CoMFA and CoMSIA models of cytotoxicity data of anti-HIV-1-phenylamino-1H-imidazole derivatives. Eur J Med Chem 44:2400–2407

    Article  CAS  Google Scholar 

  24. Roy PP, Paul S, Mitra I, Roy K (2009) On two novel parameters for validation of predictive QSAR models. Molecules 14:1660–1701

    Article  CAS  Google Scholar 

  25. Roy K, Roy PP (2009) Comparative chemometric modeling of cytochrome 3A4 inhibitory activity of structurally diverse compounds using stepwise MLR, FA-MLR, PLS, GFA, G/PLS and ANN techniques. Eur J Med Chem 44:2913–2922

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research work is supported by the Natural Science Foundation of Guangdong Province (No. 9151063201000053), China.

Author information

Authors and Affiliations

  1. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, People’s Republic of China

    Ping Lan, Wan-Na Chen, Zhi-Jian Huang, Ping-Hua Sun & Wei-Min Chen

Authors
  1. Ping Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wan-Na Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhi-Jian Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ping-Hua Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei-Min Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei-Min Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lan, P., Chen, WN., Huang, ZJ. et al. Understanding the structure-activity relationship of betulinic acid derivatives as anti-HIV-1 agents by using 3D-QSAR and docking. J Mol Model 17, 1643–1659 (2011). https://doi.org/10.1007/s00894-010-0870-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-010-0870-x

Keywords

Search

Navigation