Computational Insight into the Dual AXL/MerTK Inhibition Potential of Some AXL Inhibitors

Abstract

Cancer is a multifactorial disease characterized by uncontrolled cell growth and spreading. It is still one of the leading causes of death globally. In addition to this, various side effects of the clinically available anticancer drugs and resistance developments against them have been reported. Therefore, there is an urgent need for novel drugs with high efficacy and low side effects. Tyrosine kinases are among the primary targets of research groups working in this area. MerTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. MerTK and AXL have a direct involvement in tumor cell survival, chemoresistance, and metastasis. Researches demonstrate the role of MerTK and AXL inhibitors in tumor cell inhibition and immune response modulation. Hence, dual inhibition of the two enzymes is an attractive target in the anticancer drug candidate discovery. There are efforts to discover novel chemical agents that are dual inhibitors of MerTK/AXL. In light of these findings, the inhibition potential of AXL inhibitors on MerTK was investigated through computational methods to find out their dual inhibition potency. The binding potential of the selected AXL inhibitors to MerTK was explored through molecular docking. The docking study revealed that BGB324 might have the highest binding potential to the enzyme. Hence, BGB324 is anticipated to exhibit the highest dual inhibition among the investigated ligands. Furthermore, the interaction of the selected inhibitors to the enzyme via Asp741 was found to be critical in their binding. Molecular electrostatic potential and frontier molecular orbital appraisal of the selected inhibitors were also undertaken through density functional theory (DFT). The DFT study demonstrated that BGB324 would exhibit the highest chemical stability. The computational study findings need confirmation by further in vitro and in vivo studies.