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
Keywords: PPARs, Specs database, molecular docking, ADMET, MD simulations, CBP.
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