%0 Journal Article
%T SAR and Computer-Aided Drug Design Approaches in the Discovery of Peroxisome Proliferator-Activated Receptor ¦Ã Activators: A Perspective
%A Vaibhav A. Dixit
%A Prasad V. Bharatam
%J Journal of Computational Medicine
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/406049
%X Activators of PPAR¦Ã, 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Rosiglitazone (RGZ), and Pioglitazone (PGZ) were introduced for treatment of Type 2 diabetes, but TGZ and RGZ have been withdrawn from the market along with other promising leads due cardiovascular side effects and hepatotoxicity.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 PPAR¦Ã and its interactions with potential ligands maintain the importance of PPAR¦Ã 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 PPAR¦Ã 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 PPAR¦Ã at SER273 by ligands is reviewed as a new strategy to identify novel drug candidates. 1. Introduction to Diabetes Diabetes is a metabolic disorder caused mainly by insulin resistance and obesity. It is now recognized as a major health problem worldwide and affects adults of working age in developing countries. WHO estimates of global prevalence are expected to increase from 171 million in 2000 to 366 million in 2030, and 21.7% (i.e., ~8 crores) of these will be Indians [1]. The chronic nature of this disease leads to metabolic complications like kidney failure and cardiac problems. Early diagnosis and controlled diet combined with physical exercise of just thirty minutes have been shown to provide control in the progression of the disease. Increasing technological advancements and decreasing proportion of physical activities in routine life are promoting sedentary lifestyle. Thus pharmacological intervention may remain the only choice in certain group of subjects. In addition lack of proper treatment and delayed diagnosis are the two major reasons for the increased economic burden and prevalence of diabetes in the developing countries. Diabetes is generally classified into three classes: (1) Type 1¡ªcaused by complete lack of insulin
%U http://www.hindawi.com/journals/jcm/2013/406049/