Exploring Novel 1-Hydroxynaphthalene-2-Carboxanilides Based Inhibitors Against C-Jun N-Terminal Kinases Through Molecular Dynamic Simulation and WaterSwap Analysis.

Abstract

Cancer is a disease of mutation and lifestyle modifications. A large number of normal genes can transform normal cells to cancer cells due to their deregulations including overexpression and loss of expression. Signal transduction is a complex signaling process that involves multiple interactions and different functions. C-Jun N-terminal kinases (JNKs) is an important protein involved in signaling process. JNK mediated pathways can detect, integrate, and amplify various external signals that may cause alterations in gene expression, enzyme activities, and different cellular functions that affect cellular behavior like metabolism, proliferation, differentiation, and cell survival. In this study, we performed molecular docking protocol (MOE) to predict the binding interactions of some known anticancer 1-hydroxynaphthalene-2-carboxanilides candidates. A set of 10 active compounds was retrieved after initial screening on the basis of docking scores, binding energies, and number of interactions and was re-docked in the active site of JNK protein. The results were further validated through molecular dynamics simulation and MMPB/GBSA calculations. The active compounds 4p and 5k were ranked on top. After computationally exploring interactions of 1-hydroxynaphthalene-2-carboxanilides with JNK protein, we believe compounds 4p and 5k can serve as potential inhibitors of JNK protein. It is believed that the results of current research would help to develop novel and structurally diverse anticancer compounds that will be useful not only treat cancer but also for the medication for the other diseases caused by protein deregulation.