Journal of Computer-Aided Molecular Design

, Volume 20, Issue 5, pp 281–293 | Cite as

Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues

  • Zhenshan Zhang
  • Mingyue Zheng
  • Li Du
  • Jianhua Shen
  • Xiaomin Luo
  • Weiliang Zhu
  • Hualiang Jiang
Original Paper

Abstract

To find useful information for discovering dual functional inhibitors against both wild type (WT) and K103N mutant reverse transcriptases (RTs) of HIV-1, molecular docking and 3D-QSAR approaches were applied to a set of twenty-five 4,1-benzoxazepinone analogues of efavirenz (SUSTIVA®), some of them are active against the two RTs. 3D-QSAR models were constructed, based on their binding conformations determined by molecular docking, with r2cv values ranging from 0.656 to 0.834 for CoMFA and CoMSIA, respectively. The models were then validated to be highly predictive and extrapolative by inhibitors in two test sets with different molecular skeletons. Furthermore, CoMFA models were found to be well matched with the binding sites of both WT and K103N RTs. Finally, a reasonable pharmacophore model of 4,1-benzoxazepinones were established. The application of the model not only successfully differentiated the experimentally determined inhibitors from non-inhibitors, but also discovered two potent inhibitors from the compound database SPECS. On the basis of both the 3D-QSAR and pharmacophore models, new clues for discovering and designing potent dual functional drug leads against HIV-1 were proposed: (i) adopting positively charged aliphatic group at the cis-substituent of C3; (ii) reducing the electronic density at the position of O4; (iii) positioning a small branched aliphatic group at position of C5; (iv) using the negatively charged bulky substituents at position of C7.

Keywords

HIV-1 Reverse transcriptase 3D-QSAR 4,1-Benzoxazepinones K103N mutant 

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References

  1. 1.
    Brian GT, Summers MF (1999) J Mol Biol 285:1CrossRefGoogle Scholar
  2. 2.
    Emerman M, Malim MH (1998) Science 280:1880CrossRefGoogle Scholar
  3. 3.
    Mitsuya H, Broder S (1987) Nature 325:773CrossRefGoogle Scholar
  4. 4.
    Esnouf R, Ren J, Ross C, Jones Y, Stammers D, Stuart D (1995) Nat Struct Biol 2:303CrossRefGoogle Scholar
  5. 5.
    Jones PS (1998) Antiviral Chem Chemother 9:283Google Scholar
  6. 6.
    Pedersen OS, Pedersen EB (1999) Antiviral Chem Chemother 10:285Google Scholar
  7. 7.
    Vella S, Palmisano L (2000) Antiviral Res 45:1CrossRefGoogle Scholar
  8. 8.
    Bardsley-Elliot A, Perry CM (2000) Pediatric Drugs 2:373CrossRefGoogle Scholar
  9. 9.
    Corbett JW, Ko SS, Rodgers JD, Gearhart LA, Magnus NA, Bacheler LT, Diamond S, Jeffrey S, Klabe RM, Cordova BC, Garber S, Logue K, Trainor GL, Anderson PS, Erickson-Viitanen SK (2000) J Med Chem 43:2019CrossRefGoogle Scholar
  10. 10.
    Moyle G (2001) Drugs 61:19CrossRefGoogle Scholar
  11. 11.
    Lee K, Gulick RM (2001) Curr Infec Dis Rep 3:193Google Scholar
  12. 12.
    Adkins JC, Nobel S (1998) Drugs 56:1055CrossRefGoogle Scholar
  13. 13.
    Robert WB Jr (2001) Expert Opin Investig Drugs 10:1423CrossRefGoogle Scholar
  14. 14.
    Young SD, Britcher SF, Tran LO, Payne LS, Lumma WC, Lyle TA, Huff JR, Anderson PS, Olsen DB, Carroll SS (1995) Antimicrob Agents Chemother 39:2602Google Scholar
  15. 15.
    Lindberg J, Sigurdsson S, Lowgren S, Andersson HO, Sahlberg C, Noreen R, Fridborg K, Zhang H, Unge T (2002) Eur J Biochem 269:1670CrossRefGoogle Scholar
  16. 16.
    Ren J, Nichols C, Bird L, Chamberlain P, Weaver K, Short S, Stuart DI, Stammers DK (2001) J Mol Biol 312:795CrossRefGoogle Scholar
  17. 17.
    Jay AM, David DC, Abdul M, Beverly CC, Ronald MK, Steven PS (2001) Bioorg Med Chem Lett 11:619CrossRefGoogle Scholar
  18. 18.
    Chamberlain PP, Ren J, Nichols CE, Douglas L, Lennerstrand J, Larder BA, Stuart DI, Stammers DK (2002) J Virol 76:10015CrossRefGoogle Scholar
  19. 19.
    Medina-Franco JL, Rodríguez-Morales S, Juárez-Gordiano C, Hernández-Campos A, Castillo R (2004) J Comput Aided Mol Des 18:345CrossRefGoogle Scholar
  20. 20.
    De Clercq E (2001) Curr Med Chem 8:1543Google Scholar
  21. 21.
    Ding J, Das K, Moereels H, Koymans L, Andries K, Paul AJ, Atephen J, Huges H, Arnold E (1995) Struct Biol 2:407CrossRefGoogle Scholar
  22. 22.
    Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK (2000) Structure 8:1089CrossRefGoogle Scholar
  23. 23.
    Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Science 256:1783CrossRefGoogle Scholar
  24. 24.
    Ding J, Das K, Tantillo C, Zhang W, Clark ADJ, Jessen S, Lu X, Hsiou Y, Jacobo-Molina A, Andries K (1995) Structure 3:365CrossRefGoogle Scholar
  25. 25.
    Mao C, Sudbeck EA, Venkatachalam TK, Uckun FM (1999b) Antiviral Chem Chemother 10:233Google Scholar
  26. 26.
    Cocuzza AJ, Chidester DR, Cordova BC, Klabe RM, Jeffrey S, Diamond S, Weigelt CA, Ko SS, Bacheler LT, Erickson-Viitanen SK, Rodgers JD (2001) Bioorg Med Chem Lett 11:1389CrossRefGoogle Scholar
  27. 27.
    Cramer RD, Patterson DE, Bunce JD (1988) J Am Chem Soc 110:5959CrossRefGoogle Scholar
  28. 28.
    Klebe G, Abraham U (1999) J Comput Aided Mol Des 13:1CrossRefGoogle Scholar
  29. 29.
    Liu G, Zhang Z, Luo X, Shen J, Liu H, Shen X, Chen K, Jiang H (2004) Bioorg Med Chem 12:4147CrossRefGoogle Scholar
  30. 30.
    Powell MJD (1977) Math Programming 12:241CrossRefGoogle Scholar
  31. 31.
    Marsili M, Gasteiger J (1980) Croat Chem Acta 53:601Google Scholar
  32. 32.
    Gasteiger J, Marsili M (1980) Tetrahedron 36:3219CrossRefGoogle Scholar
  33. 33.
    Morris GM, Goodsell DS, Huey R, Hart WE, Halliday S, Belew R, Olson AJ (1999) AutoDock, Version 3.0.3. The Scripps Research Institute, Molecular Graphics Laboratory, Department of Molecular BiologyGoogle Scholar
  34. 34.
    Wallace AC, Laskowski RA, Thornton JM (1995) Protein Eng 8:127Google Scholar
  35. 35.
    Kim KS, Tarakeshwar P, Lee JY (2000) Chem Rev 100:4145CrossRefGoogle Scholar
  36. 36.
    Pungpo P, Hannongbua S (2000) J Mol Graphics Mod 18:581CrossRefGoogle Scholar
  37. 37.
    Corbett JW, Ko SS, Rodgers JD, Gearhart LA, Magnus NA, Bacheler LT, Diamond S, Jeffrey S, Klabe RM, Cordova BC, Garber S, Logue K, Trainor GL, Anderson PS, Erickson-viitanen SK (2000) J Med Chem 43:2019CrossRefGoogle Scholar
  38. 38.
    Campiani G, Ramunno A, Maga G, Nacci V, Fattorusso C, Novellino E (2002) Curr Pharma Des 8:615CrossRefGoogle Scholar
  39. 39.
    Urabe T, Sano K, Tanno M, Mizoguchi J, Otani M, Lee MH, Takasaki T, Kusakabe H, Imagawa DT, Nakai M (1992) J Virol Methods 40:145CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Zhenshan Zhang
    • 1
  • Mingyue Zheng
    • 1
  • Li Du
    • 1
  • Jianhua Shen
    • 1
  • Xiaomin Luo
    • 1
  • Weiliang Zhu
    • 1
  • Hualiang Jiang
    • 1
    • 2
  1. 1.Center for Drug Discovery and Design, State Key Laboratory of Drug ResearchShanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesShanghai China
  2. 2.School of PharmacyEast China University of Science and TechnologyShanghai China

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