Skip to main content

Advertisement

SpringerLink
Log in

De novo design by pharmacophore-based searches in fragment spaces

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

Abstract

De novo ligand design supports the search for novel molecular scaffolds in medicinal chemistry projects. This search can either be based on structural information of the targeted active site (structure-based approach) or on similarity to known binders (ligand-based approach). In the absence of structural information on the target, pharmacophores provide a way to find topologically novel scaffolds. Fragment spaces have proven to be a valuable source for molecular structures in de novo design that are both diverse and synthetically accessible. They also offer a simple way to formulate custom chemical spaces. We have implemented a new method which stochastically constructs new molecules from fragment spaces under consideration of a three dimensional pharmacophore. The program has been tested on several published pharmacophores and is shown to be able to reproduce scaffold hops from the literature, which resulted in new chemical entities.

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
Fig. 14

Similar content being viewed by others

Notes

  1. LeapFrog, Tripos L.P., St.Louis, MO (USA), http://www.tripos.com.

  2. ROCS, OpenEye Scientific Software Inc., Santa Fe, NM (USA), http://www.eyesopen.com/rocs.

  3. EA-Inventor, Tripos L.P., St.Louis, MO (USA), http://www.tripos.com.

  4. MOE software suite, Chemical Computing Group, Montreal (Canada), http://www.chemcomp.com

  5. Since these calculations are independent from each other, they can be easily parallelized and take advantage of multi-core CPUs.

  6. The World Drug Index contains marketed and development drugs and can be licensed from Thomson, Philadelphia, PA (USA).

  7. Stahl et al. placed one more lipophilic sphere than we did. This was done mainly to ensure that the cavity is filled appropriately and there is no unoccupied space. This is not needed here, since Qsearch automatically rejects molecules which are too small (cf. Methods).

  8. 2008 Intel Core2 notebook with two cores at 2 GHz

References

  1. Schneider G, Fechner U (2005) Nat Rev Drug Discov 4(8):649

    Article  CAS  Google Scholar 

  2. Mauser H, Guba W (2008) Curr Opin Drug Discov Dev 11(3):365

    CAS  Google Scholar 

  3. Kutchukian P, Shakhnovich E (2010) Expert Opin Drug Discov 5(8):789

    Article  CAS  Google Scholar 

  4. Dobson C (2004) Nature 432(7019):824

    Article  CAS  Google Scholar 

  5. Schneider P, Schneider G (2003) QSAR Comb Sci 22(7):713

    Article  CAS  Google Scholar 

  6. Degen J, Wegscheid-Gerlach C, Zaliani A, Rarey M (2008) ChemMedChem 3(10):1503

    Article  CAS  Google Scholar 

  7. Mauser H, Stahl M (2007) J Chem Inf Model 47(2):318

    Article  CAS  Google Scholar 

  8. Lewell X, Judd D, Watson S, Hann M (1998) J Chem Inf Comput Sci 38(3):511

    Article  CAS  Google Scholar 

  9. Rotstein S, Murcko M (1993) J Comput Aided Mol Des 7(1):23

    Article  CAS  Google Scholar 

  10. Pearlman D, Murcko M (1993) J Comput Chem 14(10):1184

    Article  CAS  Google Scholar 

  11. Boehm H (1992) J Comput Aided Mol Des 6(1):61

    Article  CAS  Google Scholar 

  12. Todorov N, Dean P (1998) J Comput Aided Mol Des 12(4):335

    Article  CAS  Google Scholar 

  13. Degen J, Rarey M (2006) ChemMedChem 1(8):854

    Article  CAS  Google Scholar 

  14. Pierce A, Rao G, Bemis G (2004) J Med Chem 47(11):2768

    Article  CAS  Google Scholar 

  15. Pearce B, Langley D, Kang J, Huang H, Kulkarni A (2009) J Chem Inf Model 49(7):1797

    Article  CAS  Google Scholar 

  16. Fechner U, Schneider G (2006) J Chem Inf Model 46(2):699

    Article  CAS  Google Scholar 

  17. Viswanadhan V, Ghose A, Revankar G, Robins R (1989) J Chem Inf Model 29(3):163

    Article  CAS  Google Scholar 

  18. Rarey M, Stahl M (2001) J Comput Aided Mol Des 15(6):497

    Article  CAS  Google Scholar 

  19. Damewood J, Lerman C, Masek B (2010) J Chem Inf Model 50(7):1296

    Article  CAS  Google Scholar 

  20. Fechner U, Franke L, Renner S, Schneider P, Schneider G (2003) J Comput Aided Mol Des 17(10):687

    Article  CAS  Google Scholar 

  21. Renner S, Hechenberger M, Noeske T, Bocker A, Jatzke C, Schmuker M, Parsons C, Weil T, Schneider G (2007) Angew Chem (International ed. in English) 46(28):5336

    Article  CAS  Google Scholar 

  22. Todorov N, Dean P (1997) J Comput Aided Mol Des 11(2):175

    Article  CAS  Google Scholar 

  23. Lloyd D, Buenemann C, Todorov N, Manallack D, Dean P (2004) J Med Chem 47(3):493

    Article  CAS  Google Scholar 

  24. Grant J, Gallardo M, Pickup B (1996) J Comput Chem 17(14):1653

    Article  CAS  Google Scholar 

  25. Kirkpatrick S, Gelatt C, Vecchi M (1983) Science (New York) 220(4598):671

    Article  CAS  Google Scholar 

  26. Schneider G, Hartenfeller M, Reutlinger M, Tanrikulu Y, Proschak E, Schneider P (2009) Trends Biotechnol 27(1):18

    Article  CAS  Google Scholar 

  27. Maass P, Schulz-Gasch T, Stahl M, Rarey M (2007) J Chem Inf Model 47(2):390

    Article  CAS  Google Scholar 

  28. Leach A, Gillet V, Lewis R, Taylor R (2010) J Med Chem 53(2):539

    Article  CAS  Google Scholar 

  29. Spitzer G, Heiss M, Mangold M, Markt P, Kirchmair J, Wolber G, Liedl K (2010) J Chem Inf Model 50(7):1241

    Article  CAS  Google Scholar 

  30. Gmespie R (1970) J Chem Edu 47(1):18

    Article  Google Scholar 

  31. Gillet V, Willett P, Bradshaw J (2003) J Chem Inf Comput Sci 43(2):338

    Article  CAS  Google Scholar 

  32. Stahl M, Rarey M (2001) J Med Chem 44(7):1035

    Article  CAS  Google Scholar 

  33. Kurumbail R, Stevens A, Gierse J, McDonald J, Stegeman R, Pak J, Gildehaus D, Miyashiro J, Penning T, Seibert K, Isakson P, Stallings W (1996) Nature 384(6610):644

    Article  CAS  Google Scholar 

  34. Stahl M, Todorov N, James T, Mauser H, Boehm HJ, Dean P (2002) J Comput Aided Mol Des 16(7):459

    Article  CAS  Google Scholar 

  35. Bemis G, Murcko M (1996) J Med Chem 39(15):2887

    Article  CAS  Google Scholar 

  36. Wolber G, Langer T (2005) J Chem Inf Model 45(1):160

    Article  CAS  Google Scholar 

  37. Nagar B, Hantschel O, Young M, Scheffzek K, Veach D, Bornmann W, Clarkson B, Superti-Furga G, Kuriyan J (2003) Cell 112(6):859

    Article  CAS  Google Scholar 

  38. Nogrady T, Weaver D (2005) Medicinal Chemistry. 3rd edn. Oxford University Press, New York

    Google Scholar 

  39. Shoichet B (2004) Nature 432(7019):862

    Article  CAS  Google Scholar 

  40. Stahl M, Guba W, Kansy M (2006) Drug Discov Today 11(7–8):326

    Article  CAS  Google Scholar 

  41. Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E, Ferrin T (2004) J Comput Chem 25(13):1605

    Article  CAS  Google Scholar 

Download references

Acknowledgments

TL: I would like to thank the team I worked with on the NAOMI project for the practical and emotional support: Sascha Urbaczek, Robert Fischer and Adrian Kolodzik. TSG,TL: We would like to express our gratitude for the good cooperation with the CAMM team at Roche. The fruitful discussions which we had were the foundations for the unique features in Qsearch. 3D images were created either with the UCSF Chimera package [41] or the MOE software suite.

Author information

Authors and Affiliations

  1. Center for Bioinformatics, University of Hamburg, Bundesstr. 43, 20146, Hamburg, Germany

    Tobias Lippert & Matthias Rarey

  2. Pharmaceutical Division, F. Hoffmann-La Roche Ltd, 4070, Basel, Switzerland

    Tanja Schulz-Gasch, Olivier Roche & Wolfgang Guba

Authors
  1. Tobias Lippert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tanja Schulz-Gasch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olivier Roche
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wolfgang Guba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Rarey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Rarey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lippert, T., Schulz-Gasch, T., Roche, O. et al. De novo design by pharmacophore-based searches in fragment spaces. J Comput Aided Mol Des 25, 931–945 (2011). https://doi.org/10.1007/s10822-011-9473-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-011-9473-6

Keywords

Search

Navigation