Identification of Novel PPARα/γ Dual Agonists by Virtual Screening of Specs Database

Rosiglitazone was restricted clinically due to the side effects such as edema, weight gain and cardiac failure mainly attributing to the single and selective PPARγ activation. Nowadays, multi-targeted PPARs agonists remained to be a hot topic in the antidiabetic medicinal chemistry field. In this paper, the cooperative PPARα/γ dual agonists were screened from Specs database via the flow chart of docking, ADMET prediction and molecular dynamics (MD) simulations. Representative compounds ZINC36517927 and ZINC13573581 displayed higher binding scores, better pharmacokinetic profiles and were predicted to display the best binding affinity with PPARα/γ. Complex-based pharmacophore (CBP) models showed the key interactions in the PPARα/γ active sites. 20 ns simulations performed to the PPAR-ligand complexes indicated a stable binding conformation. This work provided an approach to identify novel high-efficiency PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).