Journal of Computer-Aided Molecular Design

, Volume 20, Issue 5, pp 333–341 | Cite as

A novel workflow for the inverse QSPR problem using multiobjective optimization

Original Paper


A workflow for the inverse quantitative structure–property relationship (QSPR) problem is reported in this paper for the de novo design of novel chemical entities (NCE) in silico through the application of existing QSPR models to calculate multiple objectives, including prediction confidence measures, to be optimized during the de novo design process. Two physical property datasets are applied as case studies of the inverse QSPR workflow (IQW): mean molecular polarizability and aqueous solubility. The case studies demonstrate the optimization of molecular structures to within a property range of interest; the optimized structures are then validated against QSPR models that are generated from sets of alternative descriptors to those used in the IQW. The paper concludes with a discussion of the results from the case studies.


Inverse QSPR problem QSAR Genetic algorithms De novo design Partial least squares regression 



This research has been supported by a Marie Curie Fellowship of the European Community programme ‘Exploring leads in combinatorial catalysis for novel clean pharmaceutical/fine chemical processes’ under contract number HPMI-CT-2001-00108.


  1. 1.
    Federsel H-J (2003) Curr Opin Drug Discov Dev 6:838–847Google Scholar
  2. 2.
    McKay B, Hoogenraad M, Damen EWP, Smith AA (2003) Curr Opin Drug Discov Dev 6:966–977Google Scholar
  3. 3.
    Venkatasubramanian V, Chan K, Caruthers JM (1995) J Chem Inf Comput Sci 35:188–195CrossRefGoogle Scholar
  4. 4.
    Skvortsova MI, Baskin II, Slovokhotova OL, Palyulin VA, Zefirov NS (1993) J Chem Inf Comput Sci 33:630–634CrossRefGoogle Scholar
  5. 5.
    Kamphausen S, Höltge N, Wirsching F, Morys-Wortmann C, Riester D, Goetz R, Thürk M, Schwienhorst A (2002) Comput-Aid Mol Design 16:551–567CrossRefGoogle Scholar
  6. 6.
    de Julián-Ortiz JV (2001) Combinator Chem High Throughput Screen 4:295–310Google Scholar
  7. 7.
    Schneider G, Fechner U (2005) Nat Rev Drug Discov 4:649–663CrossRefGoogle Scholar
  8. 8.
    Brown N, McKay B, Gilardoni F, Gasteiger J (2004) J Chem Inf Comput Sci 44:1079–1087CrossRefGoogle Scholar
  9. 9.
    Brown N, McKay B, Gasteiger J (2004) J Comput-Aid Mol Des 18:761–771CrossRefGoogle Scholar
  10. 10.
    Johnson MA, Maggiora GM (1990). Concepts and applications of molecular similarity. Wiley, New York, NYGoogle Scholar
  11. 11.
    Miller KJ (1990) J Am Chem Soc 112:8533–8542CrossRefGoogle Scholar
  12. 12.
    Huuskonen J, Salo M, Taskinen J (1998) J Chem Inf Comput Sci 38:450–456CrossRefGoogle Scholar
  13. 13.
    Brown N, McKay B, Gasteiger J (2005) QSAR Comb Sci 24:480–484CrossRefGoogle Scholar
  14. 14.
    Geladi P, Kowalski BR (1986) Anal Chim Acta 185:1–17CrossRefGoogle Scholar
  15. 15.
    The SIMCA-P software is available from Umetrics, A.B. at Scholar
  16. 16.
    Eriksson L, Johansson E, Kettaneh-Wold N, Wold S (xxxx) Introduction to multi- and megavariate data analysis using projection methods (PCA & PLS)Google Scholar
  17. 17.
    Eriksson L, Jaworska J, Worth AP, Cronin MTD, McDowell RM, Gramatica P (2003) Environ Health Perspect 111:1361–1375CrossRefGoogle Scholar
  18. 18.
    Fonseca CM, Fleming PJ (1993) In: Forrest S (ed) Genetic algorithms: proceedings of the fifth international conference. San Mateo, CA, Morgan Kaufmann, pp 416–423Google Scholar
  19. 19.
    Handschuh S, Wagener M, Gasteiger J (1998) J Chem Inf Comput Sci 38:220–232CrossRefGoogle Scholar
  20. 20.
    Agrafiotis DK (2001) IBM J Res Dev 45:545–566CrossRefGoogle Scholar
  21. 21.
    Wright T, Gillet VJ, Green DVS, Pickett SD (2003) J Chem Inf Comput Sci 43:381–390CrossRefGoogle Scholar
  22. 22.
    Cottrell SJ, Gillett VJ, Taylor R, Wilton DJ (2004) J Comput-Aided Mol De 18:665–682CrossRefGoogle Scholar
  23. 23.
    The Dragon software is available from Talete, Srl. at Scholar
  24. 24.
    Sutherland JJ, O’Brien LA, Weaver DF (2004) J Med Chem 47:5541–5554CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.Avantium Technologies B.V.AmsterdamThe Netherlands
  2. 2.Computer-Chemie-Centrum and the Institute for Organic ChemistryUniversity of Erlangen-NürnbergErlangenGermany

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