Is there a link between selectivity and binding thermodynamics profiles?

•The relationship between selectivity and binding thermodynamics is investigated.•Selectivity optimizations on eight different targets were analyzed.•Broad selectivity profiles of 19 drugs acting on six targets were analyzed.•More-favorable binding enthalpy suggests higher specificity and lower promiscuity. Thermodynamics of ligand binding is influenced by the interplay between enthalpy and entropy contributions of the binding event. The impact of these binding free energy components, however, is not limited to the primary target only. Here, we investigate the relationship between binding thermodynamics and selectivity profiles by combining publicly available data from broad off-target assay profiling and the corresponding thermodynamics measurements. Our analysis indicates that compounds binding their primary targets with higher entropy contributions tend to hit more off-targets compared with those ligands that demonstrated enthalpy-driven binding.