Targeted anticancer potential of oxazole derivative against breast cancer: Synthesis, molecular docking, dynamics simulation, and in vitro evaluation on ERBB3 receptor

The study investigates 5- ((2-nitrobenzylidene) amino 2-phenyloxazole-4-carbonitrile (PS13), a derivative of the oxazole that was designed to block the ERBB3 receptor that plays a role in breast cancer development. The syntheses of PS13 were performed in two steps due to condensation and its structure was verified with the help of IR NMR, MS, and elemental analysis. Strong binding affinity was observed between the molecules and ERBB3 with the docking score of −9.5 kcal/mol that was reinforced by the presence of key hydrogen and hydrophobic bonds. Simulation of molecular dynamics above 500 ns showed that the formation of the ligand-receptor complex was stable, and the fluctuations of RMSD were minimal, which proves the structural compatibility of the molecules and the stability of their interaction. The ADMET profiling predicted good drug-like, gastrointestinal absorption, non-P-gp substrate, and good metabolism. The analysis of density functional theory indicated that the HOMO-LUMO energy gap is −2.27 eV, which indicated the stability of the electronics, and the ability to be reactive. The PS13-SLNs that were developed were PS13-loaded solid lipid nanoparticles that had high encapsulation efficiency (81 +/- 2.16 %), and enhanced release profiles in both the acidic and neutral pH conditions. Both in vitro MTT assays of MCF-7 cells and morphological changes depicted the dose-dependent cytotoxicity with 60.27 ± 0.04 µg/mL of IC50, and morphological changes that were consonant to apoptosis. Drug release kinetics indicated a first-order mechanism and Fickian diffusion, suggesting a controlled release profile. All these combined with the high ERBB3 binding affinity, good pharmacokinetics, stable SLN formulation, and in vitro anticancer efficacy of PS13, indicate that PS13 is a promising lead candidate to advance in preclinical development in the treatment of breast cancer.