Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone

Abstract

The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research.

Keywords:

• PPARs
• diabetes
• docking
• molecular dynamics simulation
• ADMET

Acknowledgments

This work was supported by the National Natural Science Foundation of China (21202120), a China Postdoctoral Science Foundation funded project (2012T50237). The authors wish to thank the anonymous reviewers for their valuable suggestions, which were very helpful for strengthening the presentation of this study.

Disclosure

The authors report no conflicts of interest in this work.