4PVU

Crystal structure of the complex between PPARgamma-LBD and the R enantiomer of Mbx-102 (Metaglidasen)

Summary for 4PVU

• Entry DOI: 10.2210/pdb4pvu/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, (2R)-(4-chlorophenyl)[3-(trifluoromethyl)phenoxy]ethanoic acid (3 entities in total)
• Functional Keywords: alpha-helices, small four-stranded beta-sheet, activator, tdna-binding, nucleus, obesity, receptor, transcription, transcription regulation
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 65718.33

Authors

Pochetti, G.,Montanari, R.,Capelli, D.,Loiodice, F.,Laghezza, A.,Piemontese, L.,Lavecchia, A. (deposition date: 2014-03-18, release date: 2015-02-11, Last modification date: 2023-11-08)

Primary citation

Laghezza, A.,Montanari, R.,Lavecchia, A.,Piemontese, L.,Pochetti, G.,Iacobazzi, V.,Infantino, V.,Capelli, D.,De Bellis, M.,Liantonio, A.,Pierno, S.,Tortorella, P.,Conte Camerino, D.,Loiodice, F.
On the metabolically active form of metaglidasen: improved synthesis and investigation of its peculiar activity on peroxisome proliferator-activated receptors and skeletal muscles.
Chemmedchem, 10:555-565, 2015

PubMed Abstract: Metaglidasen is a fibrate-like drug reported as a selective modulator of peroxisome proliferator-activated receptor γ (PPARγ), able to lower plasma glucose levels in the absence of the side effects typically observed with thiazolidinedione antidiabetic agents in current use. Herein we report an improved synthesis of metaglidasen's metabolically active form halofenic acid (R)-2 and that of its enantiomer (S)-2. The activity of the two stereoisomers was carefully examined on PPARα and PPARγ subtypes. As expected, both showed partial agonist activity toward PPARγ; the investigation of PPARα activity, however, led to unexpected results. In particular, (S)-2 was found to act as a partial agonist, whereas (R)-2 behaved as an antagonist. X-ray crystallographic studies with PPARγ were carried out to gain more insight on the molecular-level interactions and to propose a binding mode. Given the adverse effects provoked by fibrate drugs on skeletal muscle function, we also investigated the capacity of (R)-2 and (S)-2 to block conductance of the skeletal muscle membrane chloride channel. The results showed a more beneficial profile for (R)-2, the activity of which on skeletal muscle function, however, should not be overlooked in the ongoing clinical trials studying its long-term effects.

PubMed: 25641779
DOI: 10.1002/cmdc.201402462

Experimental method

X-RAY DIFFRACTION (2.6 Å)