The eicosanoids are biologically active biomolecules involved in many diverse signaling pathways and have key roles in mammalian immunity and inflammation. It has recently been shown that parallel pathways exist in the model organism, Drosophila melanogaster, for the synthesis of these important biomolecules. One of the downstream effectors of eicosanoid signaling in mammals is the nuclear receptor PPARγ, which can bind to several ligands including eicosanoid derivatives. The activation of PPARγ by these ligands is of biomedical relevance since it is implicated in inhibiting the growth of human cancer cell lines. However, no one has studied the interactions of the fly receptor with these lipid mediators. In this study, computational tools were used to model the fly receptor, E75B and explored the binding of the eicosanoids, 13-HODE and 13-EFOXL2 to its ligand-binding domain. The analysis, showed that the ligand-binding domain of E75B has structural similarity and a comparable electrostatic profile as the ligand-binding domain of PPAR-γ. In addition, it exhibits binding to 13-HODE in the same binding pocket as PPAR-γ, curiously with enhanced interactions. This study establishes E75B as a suitable candidate for future studies in understanding its interaction with eicosanoid-derived mediators of biomedical relevance.