Broad-scale analysis of thermodynamic signatures in medicinal chemistry: are enthalpy-favored binders the better development option?

Thermodynamic profiles of ligand binding, particularly enthalpically favored binding signatures, have been suggested as a criterion to support the decision-making process around which compounds to select for further optimization in drug development. The concept was enthusiastically taken up, but turned out to be too superficial, either because many aspects determining thermodynamic profiles are insufficiently appreciated or because it is difficult to compare such data on a global scale. The impact of water, changes in protonation states, along with buffer dependencies and incompatible measurement conditions that are far from standard conditions hamper such broad-scale comparisons. However, thermodynamic signatures can make us aware of the impact of these aspects and provide important hints for improving our understanding of the binding process and defining criteria for drug optimization.