N-aryl oleamides derived from indonesian palm oil as anticancer agents: from in silico design to synthesis and in vitro assay.

Fatty acid synthase (FASN) is overexpressed in many cancers and has therefore emerged as a potential target for anticancer drug development, particularly through inhibition of the thioesterase domain. In this study, 21 N-aryl oleamide derivatives were rationally designed and screened via molecular docking against the thioesterase (TE) domain of FASN. N-phenyloleamide (OA2) and N-(o-tolyl)oleamide (OA3) emerged as the top candidates and were further evaluated in their epoxidized forms: 8-(3-octyloxiran-2-yl)-N-phenyloctanamide (EOA2) and 8-(3-octyloxiran-2-yl)-N-(o-tolyl) octanamide (EOA3). The epoxide derivatives exhibited enhanced binding affinities (OA2 = - 5.49, OA3 = - 5.36, EOA2 = - 5.85, and EOA3 = - 5.84 kcal/mol), with EOA2 showing interactions with the catalytic triad (Ser2308, Asp2338, His2481), suggesting a favorable binding orientation. The selected compounds (OA2, OA3, EOA2, and EOA3) were synthesized and evaluated for cytotoxic activity. EOA2 demonstrated the most potent activity against HeLa cells (IC50 = 6.16 µg/mL) and showed notable selectivity over normal Vero cells. Molecular dynamics simulations over 300 ns confirmed stable binding, as evidenced by consistent root mean square deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, and hydrogen-bond profiles. Molecular mechanics Poisson-Boltzmann surface area analysis showed a favorable binding free energy of - 27.62 ± 2.44 kcal/mol, indicating that hydrophobic and electrostatic interactions stabilize the complex. Protein secondary structure and Ramachandran analyses further confirmed preservation of protein structural integrity throughout the simulation, while ADMET predictions indicated acceptable drug-likeness. These findings suggest EOA2 as a promising anticancer lead compound with cytotoxic activity against HeLa cells and good selectivity toward cancer cells.