Bindings of PPARγ ligand-binding domain with 5-cholesten-3β, 25-diol, 3-sulfate: accurate prediction by molecular simulation.

Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been identified as an attractive target for atherosclerosis intervention. Given potential relevance of 5-cholesten-3β, 25-diol, 3-sulphate (CHOS) and PPARγ, an integrated docking method was used to study their interaction mechanisms, with the full considerations to distinct CHOS conformations and dynamic ensembles of PPARγ ligand-binding domain (PPARγ-LBD). The results revealed that this novel platform is satisfactory to the accurate determination of binding profiles, and the binding pattern of CHOS is rather similar as those of current PPARγ full/partial agonists. CHOS contributes to the stabilization of the AF2 and β-sheet surfaces of PPARγ-LBD and promotes the configuration adjustment of Ω loop, in order to inhibit the Cdk5-mediated PPARγ phosphorylation. Nonetheless, there are clear differences in term of occupation of full or partial agonist-like binding models. The energetic and geometric analyses further revealed that CHOS may be fond of partial agonist-like binding, and its sulfonic group and carbon skeleton are helpful for the binding process. We hope that the results will aid our understanding of recognitions involving CHOS with PPARγ-LBD and warrant the further aspects to pharmacological experiments.Communicated by Ramaswamy H. Sarma.