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
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.
Keywordsfree-energy calculations molecular dynamics simulations rational drug design
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Jérôme Hénin and Bernard Maigret are gratefully acknowledged for fruitful and motivating discussions. The authors are indebted to Robert Gilli (Université d’Aix-Marseille) for sharing the experimental micro-calorimetry data prior to publication. The Centre Informatique National de l’Enseignement Supérieur (CINES) and the centre de Calcul Réseaux et Visualisation Haute Performance (CRVHP) is acknowledged for generous provision of CPU time on their SGI Origin 3000 architectures. This work was funded in part by a Hoechst Marion Roussel sponsorship (GIP FR98 CHM 032).
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