Trametinib, a selective MEK inhibitor, is widely used in the treatment of several cancers. This study aimed to designtrametinib analogues with enhanced MEK1 inhibition using an in silico strategy. Structural modifications to the trametinib scaffold were explored through molecular docking. A library of 34 compounds was assessed, among which compounds 1C and 2R demonstrated more favorable binding energies (-12.93 kcal/mol and -13.08 kcal/mol, respectively) than trametinib (-12.00kcal/mol). These two candidates were therefore selected for further analysis. Molecular dynamics simulations showed that 1C and2R formed more stable interactions with key MEK1 residues, SER212, VAL127, and PHE209, compared to the parent drug. The analogues were further evaluated using computational pharmacokinetic and drug-likeness profiling. The lead compound, 2R,exhibited an overall efficacy profile superior to trametinib. These findings provide a strong rationale for future synthetic and biological studies aimed at improving therapeutic outcomes in MEK1-driven cancers.