Journal of Computer-Aided Molecular Design

, Volume 22, Issue 9, pp 681–691 | Cite as

A knowledge-based approach to generating diverse but energetically representative ensembles of ligand conformers

  • Roman J. Dorfman
  • Karl M. Smith
  • Brian B. Masek
  • Robert D. Clark


This paper describes a new and efficient stochastic conformational sampling method for generating a range of low-energy molecule conformations. Sampling can be tailored to a specific structural domain (e.g., peptides) by extracting torsional profiles from specific datasets and subsequently applying them to target molecules outside the reference set. The programs that handle creation of the knowledge-based torsional profiles and conformer generation per se are separate and so can be used independently or sequentially, depending on the task at hand. The conformational ensembles produced are contrasted with those generated using local minimization approaches. They are also quantitatively compared with a broader range of techniques in terms of speed and the ability to reproduce bound ligand conformations found in complexes with proteins.


Conformer generation Conformational sampling Bioactive conformation Shape-searching Docking Pharmacophores 



Many thanks to Dr. Edmond Abrahamian (Tripos) for infusing common sense into this publication, noting errors, suggesting additional areas to cover, and asking searching questions.


  1. 1.
    Smellie A, Teig SL, Towbin P (1995) J Comp Chem 16:171–187CrossRefGoogle Scholar
  2. 2.
    Cato SJ (2000) In: Güner O (ed) Pharmacophore perception, development, use in drug design. International University Line, La Jolla CA, pp 107–125Google Scholar
  3. 3.
    Beusen DD, Shands EFB, Karasek SF, Marshall GR, Dammkoehler RA (1996) J Mol Struct: Theochem 370:157–171CrossRefGoogle Scholar
  4. 4.
    Sadowski J, Gasteiger J, Klebe G (1994) J Chem Inf Comput Sci 34:1000–1008CrossRefGoogle Scholar
  5. 5.
    Meng EC, Shoichet BK, Kuntz ID (1992) J Comp Chem 13:505–524CrossRefGoogle Scholar
  6. 6.
    Venkatachalam CM, Jiang X, Oldfield T, Waldman M (2003) J Mol Graph Model 21:289–307CrossRefGoogle Scholar
  7. 7.
    Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) J Med Chem 47:1739–1749CrossRefGoogle Scholar
  8. 8.
    Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727–748CrossRefGoogle Scholar
  9. 9.
    Jones G, Willett P, Glen RC (1995) J Comput-Aided Mol Des 9: 532–549CrossRefGoogle Scholar
  10. 10.
    Hurst T (1994) J Chem Inf Comput Sci 34:190–196Google Scholar
  11. 11.
    Jain AN (2003) J Med Chem 46:499–511CrossRefGoogle Scholar
  12. 12.
    Smellie A, Kahn SD, Teig SL (1995) J Chem Inf Comput Sci 35:285–294CrossRefGoogle Scholar
  13. 13.
    Martin YC, Bures MG, Danaher EA, DeLazzer J, Lico I, Pavlik PA (1993) J Comput-Aided Mol Des 7:83–102CrossRefGoogle Scholar
  14. 14.
    Smellie A, Kahn SD, Teig SL (1995) J Chem Inf Comput Sci 35:295–304CrossRefGoogle Scholar
  15. 15.
    CONFORT® was developed by R.S. Pearlman and R. Balducci at the University of Texas, Austin, and is distributed by Tripos International, 1699 S. Hanley Rd., St. Louis MO 63144 USA (
  16. 16.
    SYBYL® and GALAHAD™ are distributed by Tripos International, 1699 S Hanley Rd, St. Louis MO 63144 USA (
  17. 17.
    OMEGA is a product of OpenEye Science Software, 3600 Cerrillos Road Suite 1107, Santa Fe NM 87508 USA (
  18. 18.
    Vieth M, Hirst JD, Brooks CL III (1998) J Comput-Aided Mol Des 6:563–572CrossRefGoogle Scholar
  19. 19.
    Perola E, Charifson PS (2004) J Med Chem 47:2499–2510CrossRefGoogle Scholar
  20. 20.
    Boström J, Norrby P-O, Liljefors T (1998) J Comput-Aided Mol Des 12:383–396CrossRefGoogle Scholar
  21. 21.
    Boström J (2001) J Comp-Aided Mol Des 15:1137–1152CrossRefGoogle Scholar
  22. 22.
    Strizhev A, Wolohan P, Choi S, Abrahamian E, Clark RD (2006) J Chem Inf Model 46:1862–1870CrossRefGoogle Scholar
  23. 23.
    KBProf and KBConf are trademarks of Tripos L.PGoogle Scholar
  24. 24.
    Nissink JW, Murray C, Hartshorn M, Verdonk ML, Cole JC, Taylor R (2002) Proteins 49:457–471CrossRefGoogle Scholar
  25. 25.
    Ash S, Cline MA, Homer RW, Hurst T, Smith GB (1997) J Chem Inf Comput Sci 37:71–79CrossRefGoogle Scholar
  26. 26.
    Homer RW, Clark RD, Hurst T, Jilek RJ, Swanson: SYBYL Line Notation (SLN): a single notation to represent chemical structures, queries, reactions, virtual libraries (manuscript in preparation)Google Scholar
  27. 27.
  28. 28.
    LeadQuest® is a available from Tripos Discovery Research Centre, Bude-Stratton Business Park, Bude Cornwall EX23 BLY UK (
  29. 29.
    Halgren TA (1996) J Comp Chem 17:490–641CrossRefGoogle Scholar
  30. 30.
    Halgren TA (1999) J Comp Chem 20:720–748CrossRefGoogle Scholar
  31. 31.
    Takahashi Y, Sukekawa M, Sasaki S-I (1992) J Chem Inf Comput Sci 32:639–643CrossRefGoogle Scholar
  32. 32.
    Gillet VJ, Willett P, Bradshaw J (2003) J Chem Inf Comput Sci 43:338–345CrossRefGoogle Scholar
  33. 33.
    Rarey M, Dixon JS (1998) J Comput-Aided Mol Des 12:471–490CrossRefGoogle Scholar
  34. 34.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) Nucl Acids Res 28:235–242 ( Scholar
  35. 35.
  36. 36.
    CONCORD® was developed by R.S. Pearlman, A. Rusinko, J.M. Skell and R. Baducci at the University of Texas, Austin, and is distributed exclusively by Tripos International, 1699 S. Hanley Rd., St. Louis MO 63144Google Scholar
  37. 37.
    Boström J, Greenwood JR, Gottfries J (2001) J Mol Graph Model 21:449–462CrossRefGoogle Scholar
  38. 38.
    McMartin C, Bohacek R (1997) J Comput-Aided Mol Des 11:333–344CrossRefGoogle Scholar
  39. 39.
    Kirchmair J, Wolber G, Laggner C, Langer T (2006) J Chem Inf Model 46:1848–1861CrossRefGoogle Scholar
  40. 40.
    Sadowski J, Boström J (2006) J Chem Inf Model 46:2305–2309CrossRefGoogle Scholar
  41. 41.
    Klebe G, Mietzner T (1994) J Comput-Aided Mol Des 8:583–606CrossRefGoogle Scholar
  42. 42.
    Krystek SR Jr, Hunt JT, Stein PD, Stouch TR (1995) J Med Chem 38:659–668CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Roman J. Dorfman
    • 1
  • Karl M. Smith
    • 1
  • Brian B. Masek
    • 1
  • Robert D. Clark
    • 1
  1. 1.Tripos Informatics Research CenterSt. LouisUSA

Personalised recommendations