Peroxisome proliferator-activated receptors α, δ and γ are a collection of ligand-activated transcription factors crucial in lipid and glucose homeostasis. The involvement of these receptors in lipid metabolism makes them perfect therapeutic target for treating obesity and stroke. In this study, ‘sum of activity’ model was employed to design multi-target agonists. We used a new strategy to design agonists that fit both α and δ but not γ, to avoid side effect. The CoMFA and CoMSIA models were used to explore the pharmacophore features by constructing three individual models: (a) α-model, (b) δ-model and (c) &gammma;-model, and two sum models: (d) α, δ- model, and (e) α, δ and γ-model. The CoMFA model yielded a significant cross validation value, q², of 0.729 and non-cross validation value, r², of 0.933 in the α, δ-model. The CoMSIA studies yielded the best predictive models with q² of 0.622 in A+S and with r² of 0.911 in the α, δ-model. Finally, we proposed that distinct features shown in models (a), (b), (d) but not (c) and (e) should be accounted in designing weight-controlling drugs.

Key words: PPAR; Sum of activities; Obesity; QSAR.