8hf8

Human PPAR delta ligand binding domain in complex with a synthetic agonist V1

spinqualitylabelsall models 8hf8, resolution 2.11Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8hf8 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.11Å Ligands: BOG, LOO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PPARD_HUMAN Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand. Publication Abstract from PubMed Peroxisome proliferator-activator receptors alpha/delta (PPARalpha/delta) are considered as potential drug targets for cholestatic liver diseases (CLD) via ameliorating hepatic cholestasis, inflammation, and fibrosis. In this work, we developed a series of hydantoin derivatives as potent PPARalpha/delta dual agonists. Representative compound V1 exhibited PPARalpha/delta dual agonistic activity at the subnanomolar level (PPARalpha EC(50) = 0.7 nM; PPARdelta EC(50) = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARdelta at 2.1 A resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, V1 showed potent anti-CLD and antifibrotic effects in preclinical models at very low doses (0.03 and 0.1 mg/kg). Collectively, this work provides a promising drug candidate for treating CLD and other hepatic fibrosis diseases. Discovery of the First Subnanomolar PPARalpha/delta Dual Agonist for the Treatment of Cholestatic Liver Diseases.,Feng Z, Xiang J, Sun G, Liu H, Wang Y, Liu X, Feng J, Xu Q, Wen X, Yuan H, Sun H, Dai L J Med Chem. 2023 Jun 8;66(11):7331-7354. doi: 10.1021/acs.jmedchem.2c02123. Epub , 2023 May 27. PMID:37243609 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA