The many contributions to protein-ligand binding: Implications in drug design

Abstract

The protein-ligand binding event is exceedingly complex with several contributions playing important roles in determining the affinities of compounds against biological targets. The net binding free energy is a fine balance between contributions that oppose binding, such as individual ligand and protein penalty terms (interactions lost with the solvent, strain, and also entropy losses), and those that favor it like protein-ligand intermolecular interactions and the release of waters from binding sites. Here, some of the most important contributions to Protein-Ligand binding are analyzed. Deep knowledge of those contributions is of fundamental importance in Medicinal Chemistry since it can enhance drug design effectiveness, enabling the generation of compounds with improved potency and desirable properties.