Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery
Haowen Jiang, X. Edward Zhou, Jingjing Shi, Zhi Zhou, Guanguan Zhao, Xinwen Zhang, Yili Sun, Kelly Suino-Powell, Lei Ma, Hui Gao, Xiyong Yu, Jia Li, Jingya Li, Karsten Melcher, H. Eric Xu, Wei Yi
Abstract
characterization of a novel, decanoic acid (DA)-based and selective PPARγ modulator (SPPARγM), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPARγ ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARγMs as safe and highly efficacious anti-diabetic drugs.