Background: The Peroxisome Proliferator-Activated Receptors (PPARs) are ligandactivated
transcription factors belonging to the nuclear receptor family. The roles of PPARα in
fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been widely
characterized. Compounds with dual PPARα/γ activity have been proposed, combining the benefits
of insulin sensitization and lipid lowering into one drug, allowing a single drug to reduce
hyperglycemia and hyperlipidemia while preventing the development of cardiovascular
Methods: The new PPARα/γ agonists were screened through virtual screening of pharmacophores
and molecular dynamics simulations. First, in the article, the constructed pharmacophore was used
to screen the Ligand Expo Components-pub database to obtain the common structural
characteristics of representative PPARα/γ agonist ligands. Then, the accepted ligand structure was
modified and replaced to obtain 12 new compounds. Using molecular docking, ADMET and
molecular dynamics simulation methods to screen the designed 12 ligands, analyze their docking
scores when they bind to the PPARα/γ dual targets, their stability and pharmacological properties
when they bind to the PPARα/γ dual targets.
Results: We performed pharmacophore-based virtual screening for 22949 molecules in Ligand
Expo Components-pub database. The compounds that were superior to the original ligand were
performed structural analysis and modification, and a series of compounds with novel structures
were designed. Using precise docking, ADMET prediction and molecular dynamics methods to
screen and verify newly designed compounds, and the above compounds show higher docking
scores and lower side effects.
Conclusion: 9 new PPARα/γ agonists were obtained by pharmacophore modeling, docking
analysis and molecular dynamics simulation.