Evaluation of 3',4'-Di-O-acetyl-cis-khellactone as a Putative Antagonist of PPARγ Using Experimental and Computational Modeling.

Obesity and Non-Alcoholic Fatty Liver Disease (NAFLD) are closely linked and constitute a growing public health concern. In this work, we evaluated the antiobesity effect of an enantiomerically enriched mixture of 3',4'-di-O-acetyl-cis-khellactone (DOAcK), a natural product derivative obtained by asymmetric synthesis. This molecule is a derivative of praeruptorin, a major component found in Arracacia tolucensis as well as many other species from the Apiaceae family. A comprehensive evaluation of DOAcK was conducted using both experimental and theoretical methods. DOAcK showed significant effects in animal models, with additional evidence of diminished expression of PPARγ. Finally, we conducted molecular modeling to elucidate the putative interaction between DOAcK and PPARγ, uncovering the significant role of the so-called Ω-loop, near the ligand binding domain. In summary, these positive findings of DOAcK demonstrate that the use of this natural product could be helpful in preventing NAFLD and obesity.