A selectivity study of polysubstituted pyridinylimidazoles as dual inhibitors of JNK3 and p38α MAPK based on 3D-QSAR, molecular docking, and molecular dynamics simulation

Within the mitogen-activated protein kinase (MAPK) 1 family, the two kinases of c-Jun N-terminal kinase 3 (JNK3) and p38 alpha MAPK have emerged in the last decades as particularly attractive therapeutic targets due to their implication in several neurodegenerative pathologic conditions. In this study, the structure and activity relationship of 60 dual JNK3/p38 alpha MAPK inhibitors was explored; three-dimensional quantitative structure-activity relationship (3D-QSAR), including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis fields (CoMSIA), was performed. From the data we got, the 3D-QSAR model (CoMFA(JNK3) with q(2) is 0.642, r(2) is 0.958; CoMSIA(JNK3) with q(2) is 0.660, r(2) is 0.963; CoMFA(p38 alpha) with q(2) is 0.605, r(2) is 0.980; CoMSIA(p38 alpha) with q(2) is 0.608, r(2) is 0.970) had good predictability. Molecular docking further revealed the binding mode of inhibitors to JNK3/p38 alpha MAPK. The results of 3D-QSAR, molecular docking, and molecular dynamics simulation also provided guidance for the discovery of new dual inhibitors of JNK3 and p38 alpha MAPK. Finally, 10 novel compounds with good potential activity and ADME/T profile were designed. Molecular dynamics simulation results validated that Met149/Lys 93/Gln 155 (JNK3) and Met109/Lys53 (p38 alpha) located in the active site play a key role for novel dual inhibitors.

Automated summary

In this study, the structure-activity relationship of 60 dual JNK3/p38α MAPK inhibitors was explored using 3D-QSAR analysis. The models showed good predictability, providing guidance for the discovery of new dual inhibitors. Molecular dynamics simulation results further validated the key roles of specific residues in the active site for novel dual inhibitors.