In silico approach for the discovery of new PPARγ modulators among plant-derived polyphenols

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a well-characterized member of the PPAR family that is predominantly expressed in adipose tissue and plays a significant role in lipid metabolism, adipogenesis, glucose homeostasis, and insulin sensitization. Full agonists of synthetic thiazolidinediones (TZDs) have been therapeutically used in clinical practice to treat type 2 diabetes for many years. Although it can effectively lower blood glucose levels and improve insulin sensitivity, the administration of TZDs has been associated with severe side effects. Based on recent evidence obtained with plant-derived polyphenols, the present in silico study aimed at finding new selective human PPARγ (hPPARγ) modulators that are able to improve glucose homeostasis with reduced side effects compared with TZDs. Docking experiments have been used to select compounds with strong binding affinity (ΔG values ranging from −10.0±0.9 to −11.4±0.9 kcal/mol) by docking against the binding site of several X-ray structures of hPPARγ. These putative modulators present several molecular interactions with the binding site of the protein. Additionally, most of the selected compounds have favorable druggability and good ADMET properties. These results aim to pave the way for further bench-scale analysis for the discovery of new modulators of hPPARγ that do not induce any side effects.

Plant-Derived Polyphenols in Human Health: Biological Activity, Metabolites and Putative Molecular Targets

“…hydrogen bond acceptor sites [179,180]. To facilitate the reader's understanding, we share the following data: a library of one million compounds, previously selected with ADMET criteria, can be tested in silico with molecular docking experiments, using Auto-Dock/vina [176] software, in one week.…”

“…Obviously, the volume of data generated makes it necessary for the user to develop his own scripts to analyze this information. We use Python scripts to select the compounds with the lowest calculated free energy ( G, Kcal/mol) as possible modulators of different protein targets [179,180].…”

“…We have applied these in silico screening techniques to select compounds from two sources, a library of olive polyphenols derived from OL extract and a library of plant-derived phenolic compounds and metabolites, as possible modulators of two proteins of pharmacological interest: the transcription factor receptor PPARgamma [179] and the AMP-activated protein kinase (AMPK) [181] (Fig. 5).…”

“…However, their administration has been associated with severe side effects, and this makes this protein a target of interest in the search for new, safe modulators using in silico screening techniques. In our first paper [179], we performed molecular docking experiments with a big library of plant-derived phenolic compounds and metabolites to select 83 candidates with free energy variations ranging from -10.0±0.6 to -11.0±0.6 kcal/mol. Some of these compounds were tested in vitro, and the best candidates displayed encouraging bioactivities (manuscript in preparation).…”

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARγ

“…PPARγ, the most thoroughly studied isoform in the treatment of metabolic syndrome [12], is widely expressed in adipose tissue, macrophages, liver, kidney and lung [13]. The binding of active ligands to PPARγ would modulate the expression of related genes, play vital role in lipogenesis, glycolipids metabolism and immune system [14].…”