Uncoupling protein 1(UCP1)plays an important role in promoting brown adipose tissue formation and strengthening function of increasing energy expenditure.Thus,activation of UCP1 has become an appealing therapeutic strategy to combat obesity and diabetes.However,there is no experimental UCP1 structure available.Therefore,in this study we predicted UCP1 structure using homology modeling strategy followed by molecular docking.Homology models were constructed using MODELLER(Discovery Studio 3.0)and validated using PROCHECK in which 91.7%residues were presented in the favoured regions.Then docking study was performed to flexibly dock seven UCP1 activators into the binding site with Autodock 4.2,The binding site was predicted based on site-directed mutagenesis studies which were reported in the literatures to explore the interactions between the activators and the modeled protein.Then,a pharmacophore model was generated for the activators with Discovery Studio 3.0(HipHop module).It includes one negatively charged center and four hydrophobic groups.This study compared and contrasted the docking results with the pharmacophore model which led to the proposal of an interaction model inside the UCP1 active site,consisting of two major and one secondary interaction points: three hydrophobic groups,a negative center and an additional hydrophobic group.All of these will guide us for the structure-based drug design of novel compounds as UCP1 activators for the treatment of obesity and diabetes.