Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation.

Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPARα is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPARα agonist and NASH patients suggested that PPARα might be a potential target for NASH therapy. This promoted us to find novel PPARα agonists. The results of virtual screening and biological evaluation identified compound A-4 as a selective PPARα agonist. It significantly regulated the target genes of PPARα involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARα ligand-binding domain (LBD) and compound A-4 were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound A-4 was well characterized as a novel lead compound for developing potent and selective PPARα agonists.