Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery

Noelia Perez Diaz, Lisa Lione, Victoria Hutter, Louise Susan Mackenzie

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Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepan-cies in understanding the complex role of PPARβ/δ in disease, having both anti‐ and pro‐effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ‐regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL‐6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L−165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL‐6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS‐induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARβ/δ agonists leads to a significant increase in Pdk−4 and Angptl−4 mRNA expression, which is significantly decreased in the presence of PPARβ/δ antagonists. Docking using computational chemistry methods indicates that PPARβ/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARβ/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co‐incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARβ/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARβ/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARβ/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production.

Original languageEnglish
Article number3158
Number of pages20
JournalInternational Journal of Molecular Sciences (IJMS)
Issue number6
Early online date19 Mar 2021
Publication statusPublished - 19 Mar 2021


  • Docking
  • GSK3787
  • GW0742
  • Gene transcription
  • Inflammation
  • Lipopolysaccharide (LPS)
  • Lung
  • Molecular docking
  • Nuclear receptor
  • PPARβ/δ
  • Pulmonary artery
  • Inflammation Mediators/metabolism
  • Benzamides/chemistry
  • Molecular Conformation
  • Male
  • PPAR-beta/agonists
  • Structure-Activity Relationship
  • Nitric Oxide/metabolism
  • Lipopolysaccharides/adverse effects
  • Pulmonary Artery/drug effects
  • Binding Sites
  • Thiazoles/chemistry
  • Gene Expression
  • Rats
  • Molecular Dynamics Simulation
  • Sulfones/chemistry
  • PPAR delta/agonists
  • Animals
  • Biomarkers
  • Protein Binding
  • Ligands
  • Molecular Docking Simulation


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