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

Abstract

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.

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis

“…The cell-based transactivation assays were performed with our previously reported method with modifications. 48 Briefly, Cos7 cells were transfected with a pBIND-PPARα (or PPARδ, or PPARγ) plasmid and a pGL4.35 with 9× Gal4 UAS Luc reporter plasmid by a chemical agent HighGene (Abclonal, China). After transfection, cells were distributed in 96-well plates to recover.…”

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

“…Detailed descriptions of the cell-based evaluation for PPARs were performed with our previously reported method. , Briefly, Cos-7 cells were transfected with a pGL4.35 with 9× Gal4 UAS Luc reporter plasmid and a pBIND-PPARα (or PPARδ, or PPARγ) plasmid according to the manufacturer’s protocol. Then, after treating tested compounds at the corresponding concentrations for 16 h, cells were lysed with lysis buffer, and Luciferase Assay Reagent (Beyotime, China) was added.…”

Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor

“…All the procedures and settings for molecular modeling were similar with those in our previous studies. − The crystal structure of ACLY in complex with NDI-091143 (PDB ID: 6O0H) was used for molecular docking. The crystal structure of ACLY contained six domains.…”