Understanding PIM-1 kinase inhibitor interactions with free energy simulation

The proviral integration site of the Moloney leukemia virus (PIM) family includes three homologous members. PIM-1 kinase is an important target in effective therapeutic interventions of lymphomas, prostate cancer and leukemia. In the current work, we performed free energy calculations to calculate the binding affinities of several inhibitors targeting this protein. The alchemical method with integration and perturbation-based estimators and the end-point methods were compared. The computational results indicated that the alchemical method can accurately predict the binding affinities, while the end-point methods give relatively unreliable predictions. Decomposing the free energy difference into enthalpic and entropic components with MBAR reweighting enabled us to investigate the detailed thermodynamic parameters with which the entropy-enthalpy compensation in this protein-ligand binding case is identified. We then studied the conformational ensemble, and the important protein-ligand interactions were identified. The current work sheds light on the understanding of the PIM-1-kinase-inhibitor interactions at the atomic level and will be useful in the further development of potential drugs.