Optimisation of Tyrosine-based Lead Molecules Capable of Modulation of the Peroxisome Proliferator-activated Receptor Gamma

The peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone has recently been withdrawn from the European market and its use has been restricted in the US due to its undesirable effects which were considered to outweigh its benefits. Literature indicates that there are two agonist bound conformations of the PPARγ as exemplified by its binding to rosiglitazone (PDB ID; 1FM6) and to farglitazar (PDB ID; 1FM9). This study aims to explore these two conformations, and to evaluate whether they should be targeted separately in the context of drug design studies. Furthermore, it was aimed to design a series of molecules with the potential to act as leads in a drug design process and the capability of agonist activity at the PPARγ with an acceptable side effect profile. In silico ligand binding affinities (pKd) of rosiglitazone and farglitazar within their cognate receptors were 6.62 and 9.70 respectively. The farglitazar conformer that bound optimally within the rosiglitazone bound PPARγ ligand binding pocket was identified and its binding affinity (pKd) re-determined. An analogous conformational analysis of rosiglitazone within the farglitazar bound PPARγ ligand binding pocket was carried out. The binding affinities (pKd) for these optimum conformations were 8.12 and 6.16 respectively. De novo novel structures were generated in silico based on the tyrosine-agonist farglitazar and its cognate ligand binding pocket. Moreover, analysis of the binding modality of farglitazar indicates that this molecule accesses the PPARγ ligand binding pocket more completely than does rosiglitazone. Binding affinity studies have shown that the PPARγ ligand binding pocket adopts diverse ligand driven conformations. INTRODUCTION: The recent advance in the development of new remedies for the treatment of type 2 diabetes mellitus is a result of the increase in the incidence of this disease, as well as the high percentage of associated co-morbidities and deaths . The thiazolidinediones are peroxisome proliferatoractivated receptor gamma (PPARγ) agonists which were designed to manage type 2 diabetes mellitus owing to their ability to improve insulin sensitivity through actions which are completely different from those of other oral hypoglycaemic drugs . Unfortunately, these drugs have been associated with a number of undesirable effects including fluid retention, weight gain , and an increase in risk of myocardial infarction .