title: 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.
abstract: 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 (pp60)src 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 (pp60)src SH2 domain.
authors.affiliation: Equipe de dynamique des assemblages membranaires, UMR CNRS/UHP 7565, Institut nancéien de chimie moléculaire, Université Henri Poincaré, BP 239, 54506, Vandoeuvre-lès-Nancy cedex, France. Christophe.Chipot@edam.uhp-nancy.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Chipot
authors.forename: Xavier
authors.initials: X
authors.lastname: Rozanska
authors.forename: Surjit B
authors.initials: SB
authors.lastname: Dixit
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013816:Thermodynamics; D018909:src Homology Domains
chemical_list: D008024:Ligands; D016392:Proto-Oncogene Proteins pp60(c-src)