In silico drug discovery of flavonoids as potential PPAR agonists in treatment of metabolic syndrome

Peroxisome proliferative activating receptors (PPARs) are a subfamily of three ligand-inducible transcription factors which are important targets in drug discovery for the treatment of metabolic syndrome (MetS). This study aimed to discover flavonoids as potential PPAR agonists. The results showed that the generated 3D-pharmacophore model for PPAR activators included four pharmacophoric features, namely one hydrophobic, two hydrogen acceptors and one hydrogen donor points, respectively. This pharmacophore model had the specificity, accuracy and sensitivity were 74%, 74% and 75%, respectively. 648 out of 3,848 flavonoid compounds satisfied all the features of the chosen pharmacophore model. Molecular docking results demonstrated that these compounds bound well in the binding site of PPARs. Among them, F85 was the most potential compound with the binding affinities of PPARα (-9.6 kcal.mol -1 ), PPARγ (-10.5 kcal.mol -1 ), PPARδ (-9.5 kcal.mol -1 ). Through forming hydrogen bonds and hydrophobic interactions with the key residues, F85 could reach deeper into the binding pocket of the receptors. Moreover, F85 was stable in the binding site of PPARs during the molecular dynamics simulations. Therefore, this compound was deemed to be potent as PPAR agonists.