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.