Table of Contents
Journal of Computational Medicine
Volume 2013 (2013), Article ID 406049, 38 pages
Review Article

SAR and Computer-Aided Drug Design Approaches in the Discovery of Peroxisome Proliferator-Activated Receptor γ Activators: A Perspective

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar, Punjab 160062, India

Received 28 November 2012; Accepted 28 January 2013

Academic Editor: Michele Migliore

Copyright © 2013 Vaibhav A. Dixit and Prasad V. Bharatam. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Activators of PPARγ, Troglitazone (TGZ), Rosiglitazone (RGZ), and Pioglitazone (PGZ) were introduced for treatment of Type 2 diabetes, but TGZ and RGZ have been withdrawn from the market along with other promising leads due cardiovascular side effects and hepatotoxicity. However, the continuously improving understanding of the structure/function of PPARγ and its interactions with potential ligands maintain the importance of PPARγ as an antidiabetic target. Extensive structure activity relationship (SAR) studies have thus been performed on a variety of structural scaffolds by various research groups. Computer-aided drug discovery (CADD) approaches have also played a vital role in the search and optimization of potential lead compounds. This paper focuses on these approaches adopted for the discovery of PPARγ ligands for the treatment of Type 2 diabetes. Key concepts employed during the discovery phase, classification based on agonistic character, applications of various QSAR, pharmacophore mapping, virtual screening, molecular docking, and molecular dynamics studies are highlighted. Molecular level analysis of the dynamic nature of ligand-receptor interaction is presented for the future design of ligands with better potency and safety profiles. Recently identified mechanism of inhibition of phosphorylation of PPARγ at SER273 by ligands is reviewed as a new strategy to identify novel drug candidates.