5zxi | pdb_00005zxi
Co-crystal structure of an Inhibitor in complex with human PPARdelta LBD
Structural highlights
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.[1] [2] Publication Abstract from PubMedThe X-ray structure of the previously reported PPARdelta modulator 1 bound to the ligand binding domain (LBD) revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacement of the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selective PPARdelta modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARdelta target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients. Selective PPARdelta Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD).,Lagu B, Kluge AF, Tozzo E, Fredenburg R, Bell EL, Goddeeris MM, Dwyer P, Basinski A, Senaiar RS, Jaleel M, Tiwari NK, Panigrahi SK, Krishnamurthy NR, Takahashi T, Patane MA ACS Med Chem Lett. 2018 Jul 31;9(9):935-940. doi: 10.1021/acsmedchemlett.8b00287., eCollection 2018 Sep 13. PMID:30258544[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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