In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties

Modelling the effects of PPARβδ of innate inflammatory responses in lung tissues

“…Thus, there are multiple levels of regulation by which PPARβ/δ can influence the expression of target genes.Further to this, It has been suggested that the large ligand binding pocket of PPARβ/δ can accommodate more than one ligand, resulting in an unusual PPAR:ligand stoichiometries that could trigger inactive receptor conformations (28), a possibility that was further investigated using in silico methods.Firstly, the two PPARβ/δ agonists (GW0742 and L-165042) and two antagonists (GSK3787 and GSK0660) were docked into the PPARβ/δ binding site. It was found that the agonists and antagonists have a different binding profile within the binding pocket: the same three amino acids His287, His413 and Tyr437 form polar interactions with the two agonists tested -but they do not bind the antagonists -and the amino acids Thr252 and Asn307 are more prone to bind the antagonists.This finding agrees with previous results were GW0742 was docked to another PPARβ/δ crystal structure (PDB: 3GZ9) using another docking software (Glide), and the same three amino acids bound to GW0742(47). Furthermore, several studies co-crystallized PPARβ/δ with different agonists both synthetic, such as iloprost(48), the fibrate GW2433 (49), or GW501516 (50) and natural PPARβ/δ agonists such as with eicosapentaenoic acid (EPA)(49), and in all cases the agonists showed polar bindings with the same three amino acids His287, His413 and Tyr437.It is worth mentioning another study where the authors selected 5 compounds that potentially bound PPARβ/δ and performed a luciferase transactivation assay to biologically test if these compounds activate PPARβ/δ.…”