Protein dynamics and drug design: The role of molecular simulations

The motions of proteins underlie all processes in cells, ranging from substrate transport to signal transmission, trafficking, formation of complexes and catalysis. Taking dynamics into account in molecular recognition may hold great promise in understanding the determinants of complex formation, in the identification of new binding sites and in the discovery of new drugs. Several groups have started tackling these problems with the use of simulation methods. The study of ligandinduced dynamic variations has also been exploited to review the concept of allosteric changes. The dynamics of proteins and complexes has also been used to develop pharmacophore models based on ensembles of protein conformations. These models, taking flexibility explicitly into account, are able to distinguish active inhibitors vs nonactive drug-like compounds, to define new molecular motifs and to preferentially identify specific ligands for a certain protein target. In this chapter, examples illustrating how simulations can be used to understand dynamics in relation to ligand binding and eventually to drug design will be presented. Finally, we will present two examples illustrating the utility of including dynamics in the design process of inhibitors against a well-defined protein receptor and against the formation of self-aggregated peptide oligomers.