Abstarct: Some imine drugs bind to Ligand Binding Domain of estrogen receptor-α. On the other hand, drug binding strength is important, because binding causes a conformational change in the estrogen receptor. Therefore, we used computational method of ONIOM to obtain drug binding energy. Three-laxyer ONIOM (M06-2x/6-31+G*:PM6: AMBER) method was used for studying of drug binding. Initial models were constructed using binding sites derived from Hotspot Wizard Server and capping of their amino acids. Binding energy values demonstrated that strongest binding belong to drug of 4,4'-((o-tolylimino)methylene)diphenol and weakest binding happen with drug of 4,4'-(((2-chlorophenyl)imino)methylene)diphenol. Also, we have found that binding energy depend on substitute group on studied drugs. Moreover, interaction energy between drug and its surrounding residues were calculated by B3LYP/6-31G** method. Donor electron group’s increases electron resonance in drug structure and electron resonance causes difficult molecule rotation for creating of proper hydrogen bond. Interaction energy data showed that drug binding strength depend on hydrogen bonding with residues of Glu353, Arg394 and Thr347 and also hydrophobic interaction with other residues detected by Hotspot Wizard server.