Indazole MRL-871 interacts with PPARγ via a binding mode that induces partial agonism

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a central role in metabolic processes. PPAR gamma full agonists have side effects, arguing for the discovery of PPAR gamma partial agonists with novel chemotypes. We report the unique binding mode of the known allosteric retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) ligand MRL-871 to PPAR gamma. MRL-871 binds between PPAR gamma helices 3, 5, 7 and 11, where it stabilizes the beta-sheet region with a hydrogen bond between its carboxylic acid moiety and PPAR?? Ser370. Its unique binding mode differs from that of the benzoyl 2-methyl indoles which are well-studied, structurally similar, PPAR gamma ligands. MRL-871's high affinity for PPAR gamma induces only limited coactivator stabilization, highlighting its attractive partial agonistic characteristics. Affinity comparison of MRL-871 and related compounds towards both ROR gamma t and PPAR gamma indicates the possibility for tuning of selectivity, bringing MRL-871 forward as an interesting starting point for novel PPAR gamma ligands.

Automated summary

The nuclear receptor PPAR gamma plays a central role in metabolism, and its discovery of partial agonists with novel chemotypes is important. The unique binding mode of MRL-871 to PPAR gamma suggests its potential as a starting point for the development of novel PPAR gamma ligands.