Insights into the c-Jun N-terminal kinase 3 (JNK3) inhibitors: CoMFA, CoMSIA analyses and molecular docking studies

JNK3, a protein kinase of the MAPK family that is potently activated by a variety of environmental stress and pro-inflammatory cytokines, has been recognized as an important therapeutic target for several neurodegenerative diseases. However, due to the long development cycle and the cost of R&D, no related drugs have been released. By applying the CoMFA and CoMSIA methods, QSAR models that explore the structure-activity relationship of the JNK3 inhibitors are established and validated, the parameters are satisfactory ( q 2 = 0.774, r 2 = 0.991 for CoMFA model and q 2 = 0.666, r 2 = 0.990 for CoMSIA model) and base on which a series of novel molecules are designed. Molecular docking is conducted to verify the potential of the new compounds, the results shows promising activity. We speculated that the series of compounds S1 – S11 might have some therapeutic activity in the c-jnk3 pathway, particularly the “ S8 ” may prove to be the best one, which provided useful guidance for the design of new and efficient subtype selective JNK3 inhibitors.