Revealing the Potency of Natural Compounds as Dual Kinase Blockers by Structure-Based Modeling and Extensive MD Simulation Strategy

Abstract

Upregulation of MAPK pathway receptors has been majorly reported for the accumulation of tumor cells in non-small cell lung cancer (NSCLC) patients. Several scientific endeavors were committed to developing checkpoint inhibitors for MAPK intermediates. However, poor toxicity profiling and over-expression of other kinases diminish the treatment outcomes. Recently, dual-action drugs are developed to overcome the ineptness and drug resistance that typically occur when the usage of individual checkpoint inhibitors. Therefore, we screened 1574 natural compounds from the NPACT database using high-end computational tools against these attractive kinase targets (RAF and MEK). Initially, Glide docking and prime-MM/GBSA analysis yielded a total of seven hit compounds that showed better binding potency on both targets. The van der Waals interaction energy highly favors the binding of the compound with respective target receptors. Later, we used dynamics ensembles to examine the essential and stable interactions in the complex structures through 16 different MD simulations (50[Formula: see text]ns) cumulatively in both RAF and MEK systems. These extensive MD analyses resulted in two lead compounds such as NPACT00282 and NPACT01075 having the potential to make a stable complex with RAF and MEK receptors. Notably, the interaction of compounds with CYS532 and TYR125 in RAF and MEK, respectively, might play a crucial role in the compound’s binding process. Furthermore, these lead compounds exhibited good pharmacokinetic/dynamic characteristics. Collectively, we believe that these lead compounds are able to provide better therapeutic options and thus overcome the shortcomings in lung cancer treatment.