5-Lipoxygenase inhibitors are of current interest for asthma therapy and inflammatory diseases. In order to identify the essential structural and physicochemical requirements in terms of common biophoric sites (pharmacophore) and secondary sites for binding and interacting with 5-lipoxygenase, a series of 51 compounds of chalcones has been used for the development of 3D-QSAR models on APEX-3D expert system. Among several models, the two models have been identified with the statistical criteria R(2)>0.75, Chance <0.001 and Match >0.7. Both the models (nos 1 and 2) with three biophoric sites and four secondary sites, showed very good correlation (r>0.9) between the observed and calculated or predicted activities.