Homology modeling, virtual screening and MD simulations for the identification of NUAK1 and ULK1 potential dual inhibitors

Abstract

Cancer cells produce more reactive oxygen species (ROS) due to their severe metabolic stress. SNF1-like kinase 1 (NUAK1) is a key component of the cellular antioxidant system. Inhibiting the antioxidant system can increase the ROS level and lead to lethal oxidative stress, inducing cancer cell apoptosis; therefore, NUAK1 has been considered an attractive target for cancer treatment. However, oxidative stress can activate the protective autophagy of cancer cells through the UNC-51-like kinase 1 (ULK1) pathway, and the effect of inhibiting NUAK1 is far from satisfying. In recent years, an increasing number of studies have confirmed that the combined inhibition of NUAK1 and ULK1 increases the ROS level significantly in cancer cells and animal models. Hence, dual-targeted inhibitors of NUAK1 and ULK1 can improve the efficacy of drugs targeting antioxidant systems. In this study, 2 327 874 drug-like compounds were screened by pharmacophore screening, molecular docking, and toxicity prediction. Finally, 5 hits with dual-targeted inhibition potential and good security were obtained. The results of molecular dynamics simulations and BFE calculations indicate that compound 1 is the most promising hit. Future experimental studies are recommended to confirm the efficacy of compound 1.