A Systematic Analysis of the Binding Affinity between the Pim-1 Kinase and Its Inhibitors Based on the MM/3D-RISM/KH...

A systematic study of the binding affinities of 16 lead compounds targeting the Pim-1 kinase based on the 3D-RISM/KH theory and MD simulations is reported. The results show a correlation coefficient R = 0.69 between the theoretical and experimental values of the binding free energy. This demonstrates that the method is applicable to the problem of compound screening and lead optimization, for which relative values of the free energy among the compounds have significance. We elucidate the contribution of the ligand fragments to the binding free energy. Our results indicate that the interactions between the residues and the triazolo[4,3-b]pyridazine scaffold as well as the phenyl ring of the ligand molecule make significant contributions to stabilization of the complex. Using the 3D-RISM/KH theory, we further analyze the probability distribution of a ligand fragment around the protein-ligand complex in which the substituent around the phenyl ring is removed from the ligand. The results demonstrate that the 3D-RISM/KH theory is capable of predicting the position of substitution on a ligand that has a higher affinity to a target protein.