Skip to main content
SpringerLink
Log in

Study on improving the selectivity of compounds that inhibit two PI3Ks (gamma and delta)

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

Abstract

A desirable characteristic of PI3K inhibitors is their selectivity. Up to now, there has been no report that describes the 3 D-structure differences between two PI3Ks (δ and γ) and applies them to designing selective compounds. In the present study, we used an approach combining protein-structure modeling, GRID/PCA (Principal Component Analysis) and docking methods to investigate the detail interactions of the two PI3Ks with various chemical groups. At first, we constructed a 3 D-model of the PI3Kδ catalytic subunit with the program Modeller7.0 based on the high resolution X-ray structure of the PI3Kγ catalytic subunit, and then employed GRID and PCA to reveal the most relevant structural and physicochemical differences between the two PI3Ks related to their selectivity. As a result, the analysis unveiled the most important regions on the two PI3Ks that should be taken into account for the design of selective inhibitors. Finally, based on activity data of 10 PI3Kδ-selective compounds, a docking study validated the results of the GRID/PCA method, which suggested that the approach could provide clear guidelines for selective drug design.

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

Similar content being viewed by others

References

  1. Vanhaesebroeck B, Waterfield MD (1999) Exp Cell Res 253:239–254

    Article  PubMed  CAS  Google Scholar 

  2. Stein RC, Waterfield MD (2000) Mol Med Today 6:347–357

    Article  PubMed  CAS  Google Scholar 

  3. Stephens LR, Eguinoa A, Erdjument-Bromage H (1997) Cell 89:105–114

    Article  PubMed  CAS  Google Scholar 

  4. Krugmann S, Hawkins PT, Pryer N, Braselmann S (1997) J Biol Chem 27:17152–17158

    Google Scholar 

  5. Hirsch E, Katanaev V, Garlanda C, Azzolino O, Pirola L, Sozzani S (2000) Science 287:1049–1053

    Article  PubMed  CAS  Google Scholar 

  6. Li Z (2000) Science 287:1046–1049

    Article  PubMed  CAS  Google Scholar 

  7. Sasaki T, Irie-Sasaki J, Jones RG, Olivera-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A (2000) Science 287:1040–1046

    Article  PubMed  CAS  Google Scholar 

  8. Hirsch E, Ornella B, Philippe T, Muriel, L, Ronan C, Florella A, Matthias W (2001) FASEB J 15:2019–2021

    PubMed  CAS  Google Scholar 

  9. Clayton E, Bardi G, Bell SE, Chantry D (2002) M J Exp Med 196:753–763

    Article  CAS  Google Scholar 

  10. Jou ST, Carpino N, Takahashi Y, Roland P, Jyh-Rong C (2002) Mol Cell Biol 22:8580–8591

    Article  PubMed  CAS  Google Scholar 

  11. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W (2002) Science 297:1031–1034

    PubMed  CAS  Google Scholar 

  12. Phillips WA, Clair FS, Munday AD, Tomas RJ, Mitchell CA (1998) Cancer 83:41–47

    Article  PubMed  CAS  Google Scholar 

  13. Gershtein ES, Shatskaya VA, Ermilova VD, Kushlinsky NE (1999) Clin Chim Acta 287:59–67

    Article  PubMed  CAS  Google Scholar 

  14. Sadhu C, Masinovsky B, Dick K, Sowell CG, Sraunton DE (2003) J Immunol 170:2647–2654

    PubMed  CAS  Google Scholar 

  15. Foukasn LC, Daniele N, Ktori C (2002) J Biol Chem 277:37124–37130

    Article  PubMed  CAS  Google Scholar 

  16. Sadhu C, Dick K, Treiberg J (2001) International patent 0181346 A2

  17. Edward H Walker, Pacold ME, Perisic O, Stephens L, Hawkins PT (2000) Mol Cell 6:909–919

    Article  PubMed  CAS  Google Scholar 

  18. Djordjevic S, Driscoll PC (2002) TRENDS Biochem Sci 27:426–432

    Article  PubMed  CAS  Google Scholar 

  19. Goodford PJ (1985) J MC 28:849–857

    CAS  Google Scholar 

  20. Joliffe J (1986) Principal Component Analysis. Springer, Berlin

    Google Scholar 

  21. Wold S, Esbensen K, Geladi P (1987) Chemom Intell Lab Syst 2:37–52

    Article  CAS  Google Scholar 

  22. Bairoch A, Apweiler R (2000) Nucleic Acid Res 28:45–48

    Article  PubMed  CAS  Google Scholar 

  23. Altschul SF, Madden TL, Schaffer AA, Jinghui Z, Zheng Z, Miller W (1997) Nucleic Acid Res 25:3389–3402

    Article  PubMed  CAS  Google Scholar 

  24. Berman HM, Westbrook J, Feng Z, Gilliland G, Weissig H (2000) Nucleic Acid Res 28:235–242

    Article  PubMed  CAS  Google Scholar 

  25. Thompson JD, Higgins DG, Gibson TJ (1994) Nucleic Acid Res 22:4673–4680

    Article  PubMed  CAS  Google Scholar 

  26. Sali A, Blundell TL (1993) J Mol Biol 234:779–815

    Article  PubMed  CAS  Google Scholar 

  27. Lindahl E, Hess B, van der Spoel D (2001) J Mol Mod 7:306–317

    CAS  Google Scholar 

  28. Laskowski RA, MacArthur MW, Moss DS (1993) J Appl Cryst 26:283–291

    Article  CAS  Google Scholar 

  29. Colovos C, Yeates TO (1993) Protein Sci 2:1511–1519

    Article  PubMed  CAS  Google Scholar 

  30. Morris GM, Goodsell DS, Halliday RS (1998) J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  31. Guex N, Peitsch MC (1997) Electrophoresis 18:2714–2723

    Article  PubMed  CAS  Google Scholar 

  32. Cerius 2 4.8 (1999) Accelrys Inc

  33. Dauber-Osguthrope P, Roberts VA, Osguthorpe DJ, Wolff J, Genest M (1988) Proteins 4:31–38

    Article  PubMed  Google Scholar 

  34. Gasteiger J, Marsili M (1980) Tetrahedron 36:3219–3228

    Article  CAS  Google Scholar 

  35. Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, Weiner P (1984) J Am Chem Soc 106:765–773

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge financial support from the National Natural Science Foundation of China (No.30171088), Shanghai Key Disciplinary Foundation and “863” Project of China (No.2001 AA215261).

Author information

Authors and Affiliations

  1. State Key Laboratory of Bioreactor Engineering, New World Institute of Biotechnology, 130 Mei-Long Road, Shanghai, 200237, People’s Republic of China

    Rong-Ren Kuang, Feng Qian & Dong-Zhi Wei

  2. Institute of Pesticides and Pharmaceuticals, East China University of Science and Technology, 130 Mei-Long Road, Shanghai, 200237, People’s Republic of China

    Zhong Li

Authors
  1. Rong-Ren Kuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong-Zhi Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong-Zhi Wei.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuang, RR., Qian, F., Li, Z. et al. Study on improving the selectivity of compounds that inhibit two PI3Ks (gamma and delta). J Mol Model 12, 445–452 (2006). https://doi.org/10.1007/s00894-005-0069-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-005-0069-8

Keywords

Search

Navigation