Protein-Ligand Binding Free Energies in Silico Experiments: Applications to Cases Involving FAK and FKBP12 Proteins
R. Chelli
Dipartimento di Chimica, Università degli Studi di Firenze, Firenze, Italie.
Mercredi 10 Décembre 2014, 11h00
bibliothèque LCT, tour 12 - 13, 4e étage
Improving our ability to screen large databases of compounds in silico to identify potential lead drug molecules with accurate prediction of binding affinities (free energies) could have a great impact on structure-based drug design. Here, we present recent computations made in our lab to estimate relative and absolute binding free energies of protein-ligand systems based on computer simulations with explicit solvent. Two methodologies relying on equilibrium and non-equilibrium molecular dynamics are discussed and applied to challenging cases: (1) absolute binding free energies of immunophilin FKBP12 and its I56D mutant, with FK506-related ligands, performed through Replica-Exchange simulations; (2) relative binding free energies of complexes formed by the focal adhesion kinase and some pyrrolopyrimidine-based inhibitors, performed through non-equilibrium steered molecular dynamics simulations.