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Dysregulated mRNA translation due to altered translation factors, regulators, or other components of the translation machinery is often associated with cancer proliferation, survival, invasion, angiogenesis, and metastasis. Therefore, the translation machinery is an effective target for cancer therapy. eIF4A initiation factors play an important role in translation initiation in eukaryotes. Pateamine A (PatA) is a marine natural product that inhibits cap-dependent eukaryotic translation initiation and has potent antiproliferative and proapoptotic activity. DMDAPatA (a simplified derivative of PatA) binds to plasma proteins, which limits its potency. To overcome this, a new series of PatA analogs were synthesized, and three new leads were identified with potent translation inhibitory activity. Additionally, homology models of human eIF4A1 in closed conformation were developed to understand the structural insights. PatA analogs were then docked to the predicted binding pocket, and the interactions between PatA derivatives and eiF4A1 were studied. Our computational study results suggest that PatA and its derivatives bind to a pocket located between RNA-and ATP-binding pockets. PatA analogs were found to interact with eIF4A1 residues that directly or indirectly form nonbonded interactions with RNA and ATP molecules. Additionally, these compounds interact with residues at