Theoretica chimica acta

, Volume 87, Issue 6, pp 415–430 | Cite as

Frontier orbital energies in quantitative structure-activity relationships: A comparison of quantum chemical methods

  • Brian W. Clare


The energies of the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO) have long been used as descriptors in QSAR (Quantitative Structure-Activity Relationships). It is shown that different quantum chemical methods of calculating these energies yield results which sometimes correlate poorly with each other. This could seriously affect physical interpretation of QSAR equations. A comparison is made between HOMO and LUMO energies and their differences and sums (hardness and electronegativity) calculated by some of the best knownab initio and semi-empirical methods for two series of simple organic molecules. The difference between the HOMO and LUMO energies correlates better between methods than does either alone, and their sum correlates relatively poorly. MINDO/3 (Modified Intermediate Neglect of Differential Overlap, version 3) is the poorest method in terms of correlation with the more extended basis setab initio methods, followed by CNDO (Complete Neglect of Differential Overlap) and INDO (Intermediate Neglect of Differential Overlap). The best semi-empirical methods, in terms of correlation with experiment and the more extended basis setab initio calculations, are MNDO (Modified Neglect of Differential Overlap), AM1 (Austin Model 1) and PM3 (Parametric Method 3). The simplestab initio method, STO-3G, does not agree as well with the extended basis set calculations or with experimental results as the more advanced semi-empirical methods.

Key words

QSAR HOMO LUMO Electron affinity Ionization potential Semi-empirical Ab initio frontier orbitals 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Franke R (1984) Theoretical drug design methods. Elsevier, NY, pp 115–123Google Scholar
  2. 2.
    Parr RG, Pearson RG (1983) J Am Chem Soc 105:7512Google Scholar
  3. 3.
    Pearson RG, Palke WE (1992) J Phys Chem 96:3283Google Scholar
  4. 4.
    Bushelev SN, Stepanov NF (1989) Z Naturforsch 44:212Google Scholar
  5. 5.
    Kawakami Y, Hopfinger AJ (1990) Chem Res Toxicol 3:244PubMedGoogle Scholar
  6. 6.
    Tuppurainen K, Lotjonen S, Laatikainen R, Vartiainen T, Maran U, Strandberg M, Tamm T (1991) Mutation Research 247:97PubMedGoogle Scholar
  7. 7.
    Ramos MN, Neto B de B (1990) J Comput Chem 11:569Google Scholar
  8. 8.
    Kang S, Green JP (1970) Nature 226:645PubMedGoogle Scholar
  9. 9.
    Snyder SH, Merril CR (1965) Proc Natl Acad Sci 54:258PubMedGoogle Scholar
  10. 10.
    Clare BW (1990) J Med Chem 33:687PubMedGoogle Scholar
  11. 11.
    Clare BW (1992) Unpublished dataGoogle Scholar
  12. 12.
    Szabo A, Ostlund NS (1989) Modern Quantum Chemistry, Revised First Ed., McGraw Hill, New York, pp 123–128Google Scholar
  13. 13.
    Sadlej J (1985) Semi-Empirical Methods of Quantum Chemistry, Ellis Horwood, Chichester, p 282Google Scholar
  14. 14.
    Crabbe MJC, Appleyard JR (1991) Desktop Molecular Modeller, Version 2.0, Oxford University Press, EnglandGoogle Scholar
  15. 15.
    Stewart JJP (1990) QCPE Bull 10:86Google Scholar
  16. 16.
    Dobosh P (1975) QCPE 10:281Google Scholar
  17. 17.
    Schmidt MW, Baldridge KK, Boatz JA, Jensen JH, Koseki S, Gordon MS, Nguyen KA, Windus TL, Elbert ST (1990) QCPE Bull 10:52Google Scholar
  18. 18.
    Dupis M, Spangler D, Wendoloski JJ (1980) National Resource for Computations in Chemistry Software Catalogue, University of California: Berkely, CA, USA, Program QG01Google Scholar
  19. 19.
    Gutsev GL, Boldyrev AI (1985) Adv Chem Phys 61:169Google Scholar
  20. 20.
    Stewart JJP (1990) J Comput-Aided Mol Des 4:1PubMedGoogle Scholar
  21. 21.
    Chen ECM, Wentworth WE (1974) J Chem Phys 63:3183Google Scholar
  22. 22.
    Spearman C (1913) Brit J Psychol 5:417Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Brian W. Clare
    • 1
  1. 1.School of Mathematical and Physical SciencesMurdoch UniversityMurdochAustralia

Personalised recommendations