Theoretical Exploring Selective-Binding Mechanisms of JAK3 by 3D-QSAR, Molecular Dynamics Simulation and Free Energy Calculation

Janus kinase 3 (JAK3) plays a critical role in the JAK/STAT signaling pathway and has become an attractive selective target for the treatment of immune-mediated disorders. Therefore, great efforts have been made for the development of JAK3 inhibitors, but developing selective JAK3 inhibitors remains a great challenge because of the high sequence homology with other kinases. In order to reveal the selective-binding mechanisms of JAK3 and to find the key structural features that refer to specific JAK3 inhibition, a systematic computational method, including 3D-QSAR, molecular dynamics simulation, and free energy calculations, was carried out on a series of JAK3 isoform-selective inhibitors. Necessary pharmacodynamic structures and key residues involved in efficient JAK3-inhibition were then highlighted. Finally, 10 novel JAK3 inhibitors were designed, the satisfactory predicted binding affinity to JAK3 of these analogous demonstrated that this study may facilitate the rational design of novel and selective JAK3 inhibitors.