Journal of Computer-Aided Molecular Design

, Volume 19, Issue 11, pp 765–770 | Cite as

Can free energy calculations be fast and accurate at the same time? Binding of low-affinity, non-peptide inhibitors to the SH2 domain of the src protein

  • Christophe Chipot
  • Xavier Rozanska
  • Surjit B. Dixit
Article

Summary

The usefulness of free-energy calculations in non-academic environments, in general, and in the pharmaceutical industry, in particular, is a long-time debated issue, often considered from the angle of cost/performance criteria. In the context of the rational drug design of low-affinity, non-peptide inhibitors to the SH2 domain of the pp60src tyrosine kinase, the continuing difficulties encountered in an attempt to obtain accurate free-energy estimates are addressed. free-energy calculations can provide a convincing answer, assuming that two key-requirements are fulfilled: (i) thorough sampling of the configurational space is necessary to minimize the statistical error, hence raising the question: to which extent can we sacrifice the computational effort, yet without jeopardizing the precision of the free-energy calculation? (ii) the sensitivity of binding free-energies to the parameters utilized imposes an appropriate parametrization of the potential energy function, especially for non-peptide molecules that are usually poorly described by multipurpose macromolecular force fields. Employing the free-energy perturbation method, accurate ranking, within ±0.7 kcal/mol, is obtained in the case of four non-peptide mimes of a sequence recognized by the pp60src SH2 domain.

Keywords

free-energy calculations molecular dynamics simulations rational drug design 

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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Christophe Chipot
    • 1
  • Xavier Rozanska
    • 1
    • 2
  • Surjit B. Dixit
    • 1
    • 3
  1. 1.Equipe de dynamique des assemblages membranaires, UMR CNRS/UHP 7565, Institut nancéien de chimie moléculaireUniversité Henri PoincaréVandoeuvre-lès-Nancy cedexFrance
  2. 2.Institut für ChemieHumboldt-Universität zu BerlinBerlinGermany
  3. 3.Wesleyan UniversityMiddletownUSA

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