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
Identifieur interne : 006294 ( Main/Exploration ); précédent : 006293; suivant : 006295Can 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
Auteurs : Christophe Chipot [France] ; Xavier Rozanska [France, Allemagne] ; Surjit B. Dixit [France, États-Unis]Source :
- Journal of Computer-Aided Molecular Design [ 0920-654X ] ; 2005-11-01.
English descriptors
Abstract
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.
Url:
DOI: 10.1007/s10822-005-9021-3
Affiliations:
- Allemagne, France, États-Unis
- Berlin, Connecticut, Grand Est, Lorraine (région)
- Berlin, Vandœuvre-lès-Nancy
- Université Henri Poincaré
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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.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>France</li><li>États-Unis</li></country><region><li>Berlin</li><li>Connecticut</li><li>Grand Est</li><li>Lorraine (région)</li></region><settlement><li>Berlin</li><li>Vandœuvre-lès-Nancy</li></settlement><orgName><li>Université Henri Poincaré</li></orgName></list><tree><country name="France"><region name="Grand Est"><name sortKey="Chipot, Christophe" sort="Chipot, Christophe" uniqKey="Chipot C" first="Christophe" last="Chipot">Christophe Chipot</name></region><name sortKey="Chipot, Christophe" sort="Chipot, Christophe" uniqKey="Chipot C" first="Christophe" last="Chipot">Christophe Chipot</name><name sortKey="Dixit, Surjit B" sort="Dixit, Surjit B" uniqKey="Dixit S" first="Surjit B." last="Dixit">Surjit B. 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