Application of Free Energy Perturbation (FEP) Methodology for Predicting the Binding Affinity of Macrocyclic JAK2 Inhibitor Analogues of Pacritinib

Pacritinib, an orally bioavailable macrocyclic inhibitor of Janus Kinase 2, has shown efficacy for the treatment of myelofibrosis. Due to the synthetic challenges associated with synthesizing macrocyclic analogues, we applied electrostatic complementarity, 3D-field QSAR, and free energy perturbation methods for the profiling of a set of known ligands with a view to developing a prioritization method for selecting new macrocyclic designs for synthesis. The importance of understanding the 3D conformation and flexibility of a ligand is demonstrated, with these effects having a significant implication on the accuracy of predictions.