vic-Dioxime Hydrazone Ligand as a Novel RAS/RAF/MEK/ERK Pathway Inhibitor in Colorectal Cancer: Synthesis, Characterization and In Silico Evaluation

It is aimed to perform an evaluation of a hydrazone derivative of the vic-dioxime ligand by examining its structural properties, bioactivity via molecular docking and absorption, distribution, metabolism, excretion (ADME) analysis, and stability using molecular dynamics (MD). With this respect, the innovative design, synthesis, and advanced in silico analysis of a novel vic-dioxime hydrazone ligand, (1Z,2E)-2-(hydroxyimino)-N'-[(1Z)-3,4,5-trimethoxyphenyl)methylene]ethanehydroximohydrazide (LH2) was explored. The compound was characterized through a series of spectroscopic techniques, including ¹H NMR, ¹³C NMR, FT-IR, and UV-Vis spectroscopy. In silico studies were performed to evaluate the ligand's binding affinities to major proteins of RAS/RAF/MEK/ERK signaling pathway through molecular docking. ADME profiling was conducted to assess the ligand's pharmacokinetic properties. Additionally, MD analysis was performed to evaluate the binding stability of the target-compound complex through RMSD, RMSF, RG, hydrogen bonding and MMPBSA free energy calculations. As a result of molecular docking analysis, the compound was found to have the highest binding energy value to RAS among the other target proteins RAF and ERK. In addition, it was obtained that LH2 complies with the conditions required to satisfy Lipinski's rule of five. Moreover, ERK-ligand complex exhibited the highest stability among the tested targets according to the MD simulation results. According to the results of the investigation, in silico anti-cancer activity was revealed based on molecular docking analysis and it was determined that novel vic-dioxime hydrazone ligand could act as a targeted therapeutic RAS/RAF/MEK/ERK pathway inhibitor in colorectal cancer.