Journal of Computer-Aided Molecular Design

, Volume 18, Issue 12, pp 773–784 | Cite as

Enhancing the accuracy of virtual screening: molecular dynamics with quantum-refined force fields

  • Alessandro CurioniEmail author
  • Tiziana Mordasini
  • Wanda Andreoni


A methodology aimed at improving the accuracy of current docking–scoring procedures is proposed, and validated through detailed tests of its performance in predicting the activity of HIV-1 protease inhibitors. This methodology is based on molecular dynamics simulations using a force field whose effective charges are refined by means of a novel procedure that relies on quantum-mechanical calculations and preserves the internal consistency of the parameterization scheme.


binding affinity binding energy lead optimization molecular dynamics protein–ligand interaction scoring structure-based drug design virtual screening 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lyne, P.D. 2002Drug DiscovToday71047Google Scholar
  2. 2.
    Gohlke, H., Klebe, G. 2002AngewChem. Int. Ed. Engl.412644CrossRefGoogle Scholar
  3. 3.
    McConkey, B.J., Sobolev, V., Edelman, M. 2002Curr Sci.,8383 845Google Scholar
  4. 4.
    Parr, R.G., Yang, W. 1989Density Functional Theory of Atoms and MoleculesOxford University PressNew York.Google Scholar
  5. 5.
    CPMD V3.7 Copyright IBM Corp. 1990–2003, Copyright MPI für Festkörperforschung Stuttgart 1997–2001. See Scholar
  6. 6.
    (a) Momany, F. 1984J. Phys. Chem., 82 (1978) 592; (b) Singh U.C. and Kollman, P.A.,J. Comput. Chem5129CrossRefGoogle Scholar
  7. 7.
    Mordasini, T., Curioni, A., Bursi, R., Andreoni, W. 2003ChemBioChem4155CrossRefPubMedGoogle Scholar
  8. 8.
    Holloway, M.K., Wai, J.M., Halgren, T.A, Fitzgerald, P.M.D., Vacca, J.P., Dorsey, B.D., Levin, R.B., Thompson, W.J., Chen, L.J., deSolms, S.J., Gaffin, N., Ghosh, A.K., Giuliani, E.A., Graham, S.L., Guare, J.P., Hungate, R.W., Lyle, T.A., Sanders, W.M., Tucker, T.J., Wiggins, M., Wiscount, C.M., Woltersdorf, O.W., Young, S.D., Darke, P.L. and Zugay, J.A., J. Med. Chem., 38 (1995) 305.Google Scholar
  9. 9.
    van Gunsteren, W.F., Billeter, S.R., Eising, A.A., Hünenberger, P.H., Krüger, P., Mark, A.E., Scott, W.R.P. and Tironi, I.G. Biomolecular Simulation: The GROMOS96 Manual and User Guide, vdF: Hochschulverlag AG an der ETH Zürich and BIOMOS B.V., Zürich, Switzerland, Groningen, The Netherlands, 1996, ISBN 3 7281 2422 2.Google Scholar
  10. 10.
    Berendsen, H.J.C., Postma, J.P.M., Gunsteren, W.F., Hermans, J., Pullman, B. 1981Intermolecular ForcesReidel, DordrechtThe Netherlands331342Google Scholar
  11. 11.
    Troullier, N., Martins, J.L. 1991Phys Rev. B,431993Google Scholar
  12. 12.
    Bayly, C.I., Cieplak, P., Cornell, W.D., Kollman, P.A. 1993J Phys Chem9710269CrossRefGoogle Scholar
  13. 13.
    Becke, A.D. 1988Phys. Rev. A383098PubMedGoogle Scholar
  14. 14.
    Lee, C., Yang, W., Parr, R.G. 1988Phys. Rev. B,37785Google Scholar
  15. 15.
    Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.S., Cheatham, T.E.,III, DeBolt, S., Ferguson, D., Seibel, G., Kollman, P. 1995Comp Phys. Commun.911CrossRefGoogle Scholar
  16. 16.
    Fitzgerald, P.M.D., McKeever, B.M., Van Middlesworth, J.F., Springer, J.P., Heimbach, J.C., Leu, C.-T., Herber, W.K., Dixon, R.A.F., Darke, P.L. 1990J. Biol. Chem.26514209PubMedGoogle Scholar
  17. 17.
    Lin, J.H., Ostovic, D., Vacca, J.P., Borchardt, R.T. 1998Integration of Pharmaceutical Discovery and Development: Case Studies Chapter 11Plenum PressNew York233255Google Scholar
  18. 18.
    Gunsteren, W.F., Gunsteren, W.F., Weiner, P.K. 1989Computer Simulation of Biomolecular Systems, Theoretical and Experimental ApplicationsEscom Science PublishersLeiden2759Google Scholar
  19. 19.
    Straatsma, T.P., McCammon, J.A. 1991J., Chem Phys951175Google Scholar
  20. 20.
    Beutler, T.C., Mark, A.E., Schaik, R.C., Gerber, P.R., Gunsteren, W.F. 1994Chem Phys. Lett.222529CrossRefGoogle Scholar
  21. 21.
    Hodge, C.N., Straatsma, T.P., McCammon, J.A., Wlodawer, A., Chiu, W., Burnett, R.M., Garcea, R. 1997Structural Biology of VirusesOxford University Press.New York.Google Scholar
  22. 22.
    Taylor, R.D., Jewsbury, P.J., Essex, J.W. 2002J. Comput- Aided Mol. Des.16151CrossRefPubMedGoogle Scholar
  23. 23.
    Zhou R., Friesner R.A., Ghosh A., Rizzo R.C., Jorgensen W.L., Levy R.M. (2003). J. Phys. Chem., 105 (2001) 10388; Zoete, V., Michielin O. and Karplus M., J. Comput.-Aided. Mol. Des., 17: 861.Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Alessandro Curioni
    • 1
    Email author
  • Tiziana Mordasini
    • 1
  • Wanda Andreoni
    • 1
  1. 1.IBM ResearchZurich Research LaboratoryRüschlikonSwitzerland

Personalised recommendations