Journal of Computer-Aided Molecular Design

, Volume 20, Issue 12, pp 773–788 | Cite as

Efficient overlay of small organic molecules using 3D pharmacophores

  • Gerhard Wolber
  • Alois A. Dornhofer
  • Thierry Langer
Original Paper


Aligning and overlaying two or more bio-active molecules is one of the key tasks in computational drug discovery and bio-activity prediction. Especially chemical-functional molecule characteristics from the view point of a macromolecular target represented as a 3D pharmacophore are the most interesting similarity measure when describing and analyzing macromolecule-ligand interaction. In this study, a novel approach for aligning rigid three-dimensional molecules according to their chemical-functional pharmacophoric features is presented and compared to the overlay of experimentally determined poses in a comparable macromolecule coordinate frame. The presented approach identifies optimal chemical feature pairs using distance and density characteristics obtained by correlating pharmacophoric geometries and thus proves to be faster than existing combinatorial alignment methods and creates more reasonable alignments than pure atom-based methods. Examples will be provided to demonstrate the feasibility, speed and intuitiveness of this method.


Molecular alignment Molecular superimposition Pharmacophore LigandScout 



We thank Fabian Bendix and Robert Kosara (Inte:Ligand) for their excellent work on LigandScout as well as Christian Laggner, Johannes Kirchmair, Daniela Schuster, Theodora Steindl, and Eva Kleinrath (University of Innsbruck) for testing and helpful discussions.


  1. 1.
    Krovat EM, Fruhwirth KH, Langer T (2005) J Chem Inf Model 1:146Google Scholar
  2. 2.
    Laggner C, Schieferer C, Fiechtner B, Poles G, Hoffmann RD, Glossmann H, Langer T, Moebius FF (2005) J Med Chem 15:4754CrossRefGoogle Scholar
  3. 3.
    Schuster D, Laggner C, Steindl TM, Palusczak A, Hartmann RW, Langer T (2006) J Chem Inf Model 3:1301Google Scholar
  4. 4.
    Schuster D, Laggner C, Steindl TM, Langer T (2006) Curr Drug Discov Technol 1:1CrossRefGoogle Scholar
  5. 5.
    Steindl T, Laggner C, Langer T (2005) J Chem Inf Model 3:716CrossRefGoogle Scholar
  6. 6.
    Böhm H-J, Klebe G, Kubinyi H (1996) Spektrum Akademischer VerlagGoogle Scholar
  7. 7.
    Lemmen C, Lengauer T (2000) J Comput Aided Mol Des 3:215CrossRefGoogle Scholar
  8. 8.
    Martin YC, Bures MG, Danaher EA, DeLazzer J, Lico I, Pavlik PA (1993) J Comput Aided Mol Des 1:83CrossRefGoogle Scholar
  9. 9.
    Bron C, Kerbosch J (1973) Commun ACM 9:575CrossRefGoogle Scholar
  10. 10.
    Barnum D, Greene J, Smellie A, Sprague P (1996) J Chem Inf Comput Sci 3:563CrossRefGoogle Scholar
  11. 11.
    Langer T, Krovat EM (2003) Curr Opin Drug Discov Devel 3:370Google Scholar
  12. 12.
    Langer T, Hoffmann RD (2001) Curr Pharm Des 7:509CrossRefGoogle Scholar
  13. 13.
    DS Visualizer, version 1.5, available from Accelrys, Inc., 10188 Telesis Court, Suite 100, San Diego, CA 92121, USAGoogle Scholar
  14. 14.
    Jones G, Willett P, Glen RC (1995) J Comput Aided Mol Des 6:532CrossRefGoogle Scholar
  15. 15.
    Prabhu NV, Zhu P, Sharp KA (2004) J Comp Chem 16:2049CrossRefGoogle Scholar
  16. 16.
    EON, available from OpenEye Scientific Software (, 3600 Cerrillos Rd., Suite 1107, Santa Fe, NM 87507, USAGoogle Scholar
  17. 17.
    Haigh JA, Pickup BT, Grant JA, Nicholls A (2005) J Chem Inf Model 3:673CrossRefGoogle Scholar
  18. 18.
    ROCS, available from OpenEye Scientific Software (, 3600 Cerrillos Rd., Suite 1107, Santa Fe, NM 87507, USAGoogle Scholar
  19. 19.
    Bostrom J (2001) J Comput Aided Mol Des 12:1137CrossRefGoogle Scholar
  20. 20.
    Kirchmair J, Laggner C, Wolber G, Langer T (2005) J Chem Inf Model 2:422CrossRefGoogle Scholar
  21. 21.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) Nucleic Acids Res 1:235CrossRefGoogle Scholar
  22. 22.
    Kirchmair J, Wolber G, Laggner C, Langer T (2006) J Chem Inf Model 46:1848CrossRefGoogle Scholar
  23. 23.
    Bostrom J, Greenwood JR, Gottfries J (2003) J Mol Graph Model 5:449CrossRefGoogle Scholar
  24. 24.
    Richmond NJ, Willett P, Clark RD (2004) J Mol Graph Model 2:199CrossRefGoogle Scholar
  25. 25.
    Kuhn HW (1955) Naval Res Logist Quart 2:83Google Scholar
  26. 26.
    Wolber G, Langer T (2005) J Chem Inf Model 1:160Google Scholar
  27. 27.
    Kabsch W (1976) Acta Crystal 922Google Scholar
  28. 28.
    Kabsch W (1978) Acta Crystal 827Google Scholar
  29. 29.
    Wolber G, Langer T (2001) In: Rational approaches to drug design, H.-D.H.W. Sippl, Editor. 2001, Prous Science: Barcelona, pp. 390–399Google Scholar
  30. 30.
    OMEGA, version 2.0, available from OpenEye Scientific Software (, 3600 Cerrillos Rd., Suite 1107, Santa Fe, NM 87507, USAGoogle Scholar
  31. 31.
    Cramer RD 3rd, Patterson DE, Bunce JD (1989) Prog Clin Biol Res 161Google Scholar
  32. 32.
    Kubinyi HF, G, Martin YC (1998) Vol. 1–3, Kluwer/ESCOM, DordrechtGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Gerhard Wolber
    • 1
  • Alois A. Dornhofer
    • 1
  • Thierry Langer
    • 2
  1. 1.Inte:Ligand Softwareentwickungs- und Consulting GmbHViennaAustria
  2. 2.Computer-Aided Molecular Design Group, Center of Molecular Biology InnsbruckInstitute of PharmacyInnsbruckAustria

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