Statistical molecular identification of kinase inhibitors to disrupt c‐Jun N‐terminal protein kinase involved in paraquat‐mediated toxicological effects

Paraquat is a toxic chemical that is widely used as an herbicide (plant killer), primarily for weed and grass control. Recently, kinase inhibitors have shown great potential against paraquat‐mediated toxicological effects and, specifically, the c‐Jun N‐terminal protein kinase ( JNK ) was found as a new and promising target for relieving the paraquat toxicity. Here, we developed a statistical molecular identification protocol that systematically profiles a variety of existing kinase inhibitors against JNK . A consensus molecular docking strategy was developed to examine the binding behavior of inhibitor candidates, from which top‐8 hit compounds were selected and tested; several compounds were found to show high or moderate inhibitory potency against JNK with IC 50 values at nanomolar level, which are comparable to the sophisticated JNK inhibitor SP600125. We also performed atomistic molecular dynamics simulations and post binding free energy analyses to dissect the structural basis, energetic property, and biological implication underlying the intermolecular interaction of JNK kinase domain with these promising compounds, highlighting the complicated interaction pattern between the kinase and potent hit compounds.