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Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation
journal contribution
posted on 2020-02-20, 09:13 authored by Liang Dai, Zhiqi Feng, Rili Zha, Keguang Cheng, Xiaoan Wen, Hongbin Sun, Haoliang YuanNonalcoholic 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.