Thermodynamic profiling for fragment-based lead discovery and optimization.

: The enthalpic and entropic components of the ligand-protein binding free energy reflect the type and quality of the interactions and relate to the physicochemical properties of the ligands. These findings have significance in medicinal chemistry optimizations since they suggest that the thermodynamic profiling of the binding may help monitor and control the unfavorable size and hydrophobicity increase typically accompanying affinity improvements and leading to suboptimal pharmacokinetic properties.: This review describes the ligand-protein binding event in terms of elementary steps, their associated interactions, and their enthalpic and entropic consequences. The relationships among the breaking and forming interactions, the binding thermodynamic profile, and the physicochemical properties of the ligands are also discussed.: Analysis of the size dependence of available affinity and favorable enthalpy highlights the limitation of the simultaneous optimization of these quantities. Indeed, moderate, rather than very high affinities can be conciliated with favorable physicochemical and pharmacokinetic profiles as it is supported by the affinity range of historical oral drugs. Although thermodynamic quantities are not suitable endpoints for medicinal chemistry optimizations owing to the complexity of the binding thermodynamics, thermodynamic profiling together with structural studies can be advantageously used to understand the details of the binding process and to optimize it.