6E5A

PPARg in complex with compound 4b

Summary for 6E5A

• Entry DOI: 10.2210/pdb6e5a/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, (5Z)-5-({4-[(prop-2-yn-1-yl)oxy]phenyl}methylidene)-2-sulfanylidene-1,3-thiazolidin-4-one (3 entities in total)
• Functional Keywords: ppar, nuclear receptor, transcription factor, ligand binding domain, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63119.40

Authors

Bruning, J.B.,Chua, B.S.K. (deposition date: 2018-07-19, release date: 2019-03-13, Last modification date: 2024-11-13)

Primary citation

Elzahhar, P.A.,Alaaeddine, R.,Ibrahim, T.M.,Nassra, R.,Ismail, A.,Chua, B.S.K.,Frkic, R.L.,Bruning, J.B.,Wallner, N.,Knape, T.,von Knethen, A.,Labib, H.,El-Yazbi, A.F.,Belal, A.S.F.
Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones.
Eur J Med Chem, 167:562-582, 2019

PubMed Abstract: In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC values) and moderate 15-LOX inhibitor (micromolar IC values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors.

PubMed: 30818268
DOI: 10.1016/j.ejmech.2019.02.034

Experimental method

X-RAY DIFFRACTION (2.4 Å)