Peroxisome Proliferator-Activated Receptors (PPARs) Have Multiple Binding Points That Accommodate Ligands in Various Conformations: Phenylpropanoic Acid-Type PPAR Ligands Bind to PPAR in Different Conformations, Depending on the Subtype

Abstract

Human peroxisome proliferator-activated receptors (hPPARs) are ligand-dependent transcription factors that control various biological responses, and there are three subtypes: hPPARα, hPPARδ, and hPPARγ. We report here that α-substituted phenylpropanoic acid-type hPPAR agonists with similar structure bind to the hPPAR ligand binding domain (LBD) in different conformations, depending on the receptor subtype. These results might indicate that hPPAR ligand binding pockets have multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands.

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

“…Moreover, some help to reach a better affinity and selectivity of medical compounds versus PPARs might come from the interesting studies performed with X-ray crystallographic analysis; these have shown that the high-resolution crystal structures of the PPARs complexed with these agonists will provide the structural basis for specific and versatile binding mode of these ligands [288,289]; they also might favour further development of drugs treating metabolic diseases and thus fibrosis.…”

Peroxisome proliferator-activated receptor gamma (PPARγ) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARγ partial agonists bind to PPARγ LBD in different conformations

“…These results are consistent with our proposal that the hPPARc LBD has multiple binding points that can accommodate ligands in various conformations. 12 It has been widely accepted that the binding pocket of hPPARs takes a Y-shaped cylindrical form, 13 but our results suggest that the situation might not be so straightforward.…”

Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation

“…7 In 2002, α-substituted phenylpropanoic acid-type PPAR agonists were reported to bind to the LBD in different conformations indicating multiple binding points inside the binding pocket. 8 New PPARγ scaffolds have also been reported following a virtual screening approach to identify PPAR chemotypes, however further biological studies need to be performed. 9 The oxazolidinone is a five-membered heterocyclic ring with several applications as organocatalyst and chiral auxiliary (e.g.…”

“…17 For these solutions, the oxazolidinone (CO) and carboxylic acid polar groups were close to the hydroxyl group of the lateral chain of Tyr464, which donated a hydrogen bond. The binding modes were stabilized by the hydrogen bond network with: Tyr314, Tyr464 and His440 (2, 7), Tyr 464 and His440 (3, 4, 9 and 10), Ser280, Tyr464 and His440 (8) and with the four residues just compounds 13 and 14. The chirality induced by the substituent attached to the oxazolidinone ring in position 4 is responsible for the orientation of the CO group towards the polar residues.…”

“…1) anhydrous acidic conditions giving 17 in good yields. The oxazolidinone motif was incorporated after a two-step synthesis starting from the commercially available (R)-4-benzyl-3-propionyl-2-oxazolidinone in the case of compounds (1-7) and from the (S)-4-benzyl oxazolidinone for compounds (8)(9)(10). In the first case, the use of t BuOK at room temperature triggered a crossalkylation reaction in which the oxazolidinone anion attacked the benzyl bromide derivative as we have recently reported, providing the oxazolidinone derivative 18 in moderate yields.…”