Skip to main content

Advertisement

SpringerLink
Log in

Assessing ligand efficiencies using template-based molecular docking and Tabu-clustering on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and-thione (TIBO) derivatives as HIV-1RT inhibitors

  • Published:
Journal of Chemical Sciences Aims and scope Submit manuscript

Abstract

A template-based flexible docking simulation followed by ‘Tabu-clustering’ was performed on a series of 38 TIBO derivatives as HIV-1 reverse transcriptase (HIV-1 RT) inhibitors. Four different templates of the Cl-TIBO (1-REV) were created and used as reference templates for docking and aligning. On the basis of the optimal conformation of the ligands, when fitting to the template, the respective scoring functions were obtained; different ligand efficiencies were evaluated and analysed. Statistical modelling using artificial neural network (ANN: r 2 = 0.922) and multiple linear regression method (MLR: r 2 = 0.851) showed good correlation between the biological activity, binding affinity, and different ligand efficiencies of the compounds, which suggest the robustness of the template-based binding conformations of these inhibitors. Our studies suggest that, template-based docking followed by ‘Tabuclustering’ will give a better alignment of inhibitors with respect to the crystal coordinates and enhance the docking efficiency. Also, our study indicates that scoring functions based on 3D symmetry analysis along with heavy atoms count serve as a valuable tool for estimating the efficiency of the ligands. Thus, this is a novel method based on heavy atoms count predicting the binding affinity of the TIBO group of inhibitors, so that their therapeutic utility can be enhanced.

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. O’Meara J A, Yoakim C, Bonneau P R, Bös M, Cordingley M G, Déziel R, Doyon L, Duan J, Garneau M, Guse I, Landry S, Malenfant E, Naud J, Ogilvie W W, Thavonekham B and Simoneau B 2005 J. Med. Chem. 48 5580

    Article  Google Scholar 

  2. Zheng Y H, Lovsin N and Peterlin B M 2005 Immunol. Lett. 97 225

    Article  CAS  Google Scholar 

  3. Tomasselli A G and Heinrikson R L 2000 Biochem. Biophys. Acta. 1477 189

    CAS  Google Scholar 

  4. Silvestri R and Maga G 2006 Expert Opinion on Therapeutic Patents 16 939

    Article  CAS  Google Scholar 

  5. Geitmann M, Unge T and Danielson U H 2006 J. Med. Chem. 49 2375

    Article  CAS  Google Scholar 

  6. Palella F J, Delaney K M, Moorman A C, Loveless M O, Fuhrer J, Satten G A, Ashman D J and Holmberg S D 1998 N. Engl. J. Med. 338 853

    Article  Google Scholar 

  7. Palella F J, Chmiel J S, Moorman A C and Holmberg S D 2002 AIDS 16 1617

    Article  CAS  Google Scholar 

  8. Tavel J A, Miller K D and Masur H 1999 Clin. Infect. Dis. 28 643

    Article  CAS  Google Scholar 

  9. Das K, Levi P J, Hughes S H and Arnold E 2005 Prog. Biophys. Mol. Biol. 88 209

    Article  CAS  Google Scholar 

  10. Zhou Z, Lin X and Madura J D 2006 Infectious Disorders — Drug Targets 6 391

    Article  CAS  Google Scholar 

  11. De Clercq E 1998 Antiviral Res. 38 153

    Article  Google Scholar 

  12. De Clercq E 2004 Chem. Biodiv. 1 44

    Article  Google Scholar 

  13. De Clercq E 2005 J. Med. Chem. 48 1297

    Article  Google Scholar 

  14. Kohlstaedt L A, Wang J, Friedman J M, Rice P A and Steitz T A 1992 Science 256 1783

    Article  CAS  Google Scholar 

  15. Ren J, Esnouf R, Garman E, Somers D, Ross C, Kirby I, Keeling J, Darby G, Jones Y, Stuart D and Stammers D 1995 Nature Struct. Biol. 2 293

    Article  CAS  Google Scholar 

  16. Ding J, Das K, Tantillo C, Zhang W, Clark A D J, Pauwels R, Moereels H, Koymans L, Janssen P A J, Smith R H J, Kroeger Koepke R, Michejda C J, Hughes S H and Arnold E 1995 Structure 3 365

    Article  CAS  Google Scholar 

  17. Deeks S G 2001 J. AIDS 26 S25

    CAS  Google Scholar 

  18. DeClercq E 2001 Current Medicinal Chem. 8 1543

    CAS  Google Scholar 

  19. Campiani G, Ramunno A, Maga G, Nacci V, Fattorusso C, Catalanotti B, Morelli E and Novellino E 2002 Curr. Pharmaceutical Des. 8 615

    Article  CAS  Google Scholar 

  20. Mager PP 1997 Med. Res. Rev. 17 235

    Article  CAS  Google Scholar 

  21. Tantillo C, Ding J, Jacobo-Molina A, Nanni R G, Boyer P L, Hughes S H, Pauwels R, Andries K, Janssen P A and Arnold E 1994 J. Mol. Biol. 243 369

    Article  CAS  Google Scholar 

  22. Sapre N S, Pancholi N, Gupta S and Sapre N 2008 J. Comp. Chem. DOI 10.1002/jcc 20931

  23. Sapre N S, Pancholi N, Gupta S and Sikarwar A 2007 Acta Chim. Slov. 54 797

    CAS  Google Scholar 

  24. Sapre N S, Pancholi N, Gupta S, Sikarwar A and Sapre N 2007 J. Chem. Sci. 119 625

    Article  CAS  Google Scholar 

  25. Barreca M L, Rao A, De Luca L, Zappala M, Monforte A M, Maga G, Pannecouque C, Balzarini J, De Clercq E, Chimirri A and Monforte P 2005 J. Med. Chem. 48 3433

    Article  CAS  Google Scholar 

  26. D’Cruz O J and Uckun F M 2006 J. Antimicrob. Chemother. 57 411

    Article  Google Scholar 

  27. Pauwels R, Andries K, Desmyter J, Schols D, Kukla M J, Breslin H J, Raeymaeckers A, Van Gelder J, Woestenborghs R, Heykants J, Schellekens K, Janssen M A C, De Clercq E and Janssen P A J 1990 Nature 343 47

    Article  Google Scholar 

  28. Barre-Sinoussi F, Chermann J C, Rey F, Nugeyre M T, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vezinet-Brun F, Rouzioux C, Rozenbaum W and Montagnier L 1983 Science 220 868

    Article  CAS  Google Scholar 

  29. Gallo R C et al 1984 Science 224 500

    Article  CAS  Google Scholar 

  30. Ren J, Esnouf R, Hopkins A, Ross C, Jones Y, Stammers D and Stuart D 1995 Structure 3 915

    Article  CAS  Google Scholar 

  31. Zhou Z and Madura J D 2004 J. Chem. Inf. Comput. Sci. 44 2167

    CAS  Google Scholar 

  32. Bahram H, Mohammad Hossein Tabaei S and Fatemeh N 2005 J. Mol. struct. Theochem. 732 39

    Article  Google Scholar 

  33. De Clercq E 1995 Cln. Microbiol. Rev. 8 200

    Google Scholar 

  34. Das K, Ding J, Hsiou Y, Clark, A J, Moereels H, Koymans L, Andries K, Pauwels R, Janssen P, Boyer P, Clark P, Smith R J, Kroeger S M, Michejda C, Hughes S and Arnold E 1996 J. Mol. Biol. 264 1085

    Article  CAS  Google Scholar 

  35. Ding J, Das K, Moereels H, Koymans L, Andries K, Janssen P A J, Hughes S and Arnold E 1995 Nature Struct. Mol. Biol. 2 407

    Article  CAS  Google Scholar 

  36. Saen-oon S, Kuno M and Hannongbua S 2005 Proteins 61 859

    Article  CAS  Google Scholar 

  37. Wang J, Morin P, Wang W and Kollman P A 2001 J. Am. Chem. Soc. 123 5221

    Article  CAS  Google Scholar 

  38. Pan Y, Huang N, Cho S and MacKerell A D 2003 J. Chem. Inf. Comput. Sci. 43 267

    CAS  Google Scholar 

  39. Bender A, Mussa H Y and Glen R C 2004 J. Chem. Inf. Comput. Sci. 44 1708

    CAS  Google Scholar 

  40. ChemDraw Ultra 7.0.0 (www.cambridgesoft.com)

  41. http://www.molegro.com (free trial version)

  42. Berman H M, Westbrook J, Feng Z, Gilliland G, Bhat T N, Weissig H, Shindyalov I N and Bourne P E 2000 Nucl. Acids Res. 28 235

    Article  CAS  Google Scholar 

  43. Thomsen R and Christensen M H 2006 J. Med. Chem. 49 3315

    Article  CAS  Google Scholar 

  44. Storn R and Price K 1995 Differential evolution — A simple and efficient adaptive scheme for global optimization over continuous spaces; Technical Report; International Computer Science Institute: Berkley, CA

    Google Scholar 

  45. Thomsen R 2003 Proceedings of the 2003 Congress on evolutionary computation 4 2354

    Article  Google Scholar 

  46. Gehlhaar D K, Verkhivker G, Rejto P A, Fogel D B, Fogel L J and Freer S T 1995 Proceedings of the fourth international conference on evolutionary programming 615

  47. Gehlhaar D K, Bouzida D and Rejto P 1998 Proceedings of the seventh international conference on evolutionary programming 449

  48. Yang J M and Chen C C 2004 Proteins 55 288

    Article  CAS  Google Scholar 

  49. Michalwich Z and Fogel D B 2000 How to solve it: Modern Heuristics (Berlin: Springer-Verlag)

    Google Scholar 

  50. Sapre N S, Gupta S, Pancholi N and Sapre N 2007 J. Comput. Aided Mol. Des. 22 69

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Applied Chemistry, Shri GS Institute of Technology and Sciences, Indore, 452 001, India

    Nitin S. Sapre

  2. Department of Chemistry, Govt. P.G. College, MHOW, 453 441, India

    Swagata Gupta

  3. Department of Computer Science, SD Bansal College of Technology, Indore, 453 331, India

    Neelima Sapre

Authors
  1. Nitin S. Sapre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Swagata Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neelima Sapre
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nitin S. Sapre.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sapre, N.S., Gupta, S. & Sapre, N. Assessing ligand efficiencies using template-based molecular docking and Tabu-clustering on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and-thione (TIBO) derivatives as HIV-1RT inhibitors. J Chem Sci 120, 395–404 (2008). https://doi.org/10.1007/s12039-008-0063-7

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12039-008-0063-7

Keywords

Search

Navigation