Molecular modeling studies of JNK3 inhibitors using QSAR and docking

The c-Jun N-terminal kinases (JNKs), serine/threonine protein kinases including three isoforms: JNK1, JNK2, and JNK3 are attractive targets for the treatment of neurodegenerative disorders. Many reported JNKs inhibitors could prevent neuronal degradation, but most exist with selective vulnerability to toxic effects. In this paper, we had applied a combined molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) method to understand the structural factors affecting JNK3 inhibitory potency. Docking studies were performed to explore the binding mode between 106 inhibitors and JNK3. Good correlations (r 2 = 0.933, SE = 0.502) between binding free energies and experimental inhibitory activities suggested that the binding modes of these inhibitors are reasonable. The substructure-based alignment strategy gave the reasonable 3D-QSAR models, CoMFA (q 2 = 0.752, r 2 = 0.874, r pred 2  = 0.737) and CoMSIA (q 2 = 0.789, r 2 = 0.958, r pred 2  = 0.853), whose results were consistent with the docking results. Combined 3D-QSAR and molecular docking studies provided some valuable information of intermolecular interaction to understand the structure–activity relationships of the JNK3 inhibitors, and subsequently guided the development of new potent JNK3 inhibitors.