A computational application to predict, probe and interpret the activities of a series of congeneric compounds inhibiting extracellular signal-regulated kinase 2 protein kinase is presented. The study shows that molecular dynamics coupled with molecular mechanics Poisson–Boltzmann solvent accessible surface area free energy estimation is a suitable tool for investigating the experimental binding activities of ligands to protein kinases. Computed and experimental binding activities were found to be significantly correlated. Moreover, the interpretation of the X-ray co-crystal structure in conjunction with computational results shows that the hinge region of the protein insure the principal binding site via multiple hydrogen bonding interactions, whereas fine-modulation of biological activities along the series is accomplished through the combination of weak and strong interactions that compete with water. These are located in the substituent moieties of the ligands interfacing with the DFG motif, the sugar region and the hydrophobic pocket of extracellular signal-regulated kinase 2. The study suggests that a wider interaction framework that is well beyond the hinge region is required to predict and rationalize at molecular level the experimental biological activities of congeneric compound series.