Defense Date


Document Type


Degree Name

Master of Science


Medicinal Chemistry

First Advisor

Martin Safo


The peroxisome proliferator-activated receptors (PPARs) are the transcriptional regulators of glucose, lipids and cholesterol metabolisms. It has been established that PPAR-γ is the receptor for thiazolidinediones (TZDs) class of type II anti-diabetic drugs. These compounds act as agonists of PPAR-γ. They may delay the development of type II diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. PPAR-γ receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin (responsible for glucose regulation and fatty acid metabolism) and reducing levels of inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Our goal is to take advantage of the mode of binding of known PPAR-γ agonists, such as Rosiglitazone to PPAR-γ to rationally design novel agonists of PPAR-γ. Our long-term objective is to generate new and potent PPAR-γ agonists that could be used to treat diabetes. To achieve our goal the study was divided into five specific aims, including: Aim 1. Expression and purification of PPAR-γ ligand binding domain (LBD). Aim 2. Molecular modeling to design PPAR-γ receptor modulators. Aim 3. Synthesis of potential PPAR-γ receptor modulators. Aim 4. Functional studies to determine the binding affinity of PPAR-γ receptor modulators. Aim 5. Structural studies of PPAR-γ LBD in complex with PPAR-γ receptor modulators. We expressed the His-tagged PPAR-γ LBD protein in Rosetta DE3 cells, and used a one step affinity chromatography (Ni-NTA column) to obtain a significant yield of pure protein. Using the structural features and the known binding mode of Rosiglitazone to PPAR-γ LBD as a starting point, two classes of compounds (type-I and type-II compounds) were designed as potential PPAR-γ agonists. These novel compounds were rationalized to improve on the binding modes of Rosiglitazone via additional hydrogen-bonding and/or hydrophobic interactions to the protein. Five type-I and II compounds were synthesized and tested against PPAR-γ receptor for binding affinity, using fluorescent polarization assay. The IC-50 value of the most potent compound (compound B) was found to be ~ 7-fold lower than Rosiglitazone, significantly lower than the expected value. It seems that unlike Rosiglitazone which has free rotatable thiazolidinedione ring that can make optimal interactions with His323 and His449 (two critical residues that are important for binding affinity), the thiazolidinedione ring in our compounds are fixed in one position that may not lead to optimal contact with the protein. We are currently synthesizing analogs of our compounds with rotatable thiazolidinedione ring for further studies. X-ray crystallographic study has been initiated to determine the binding modes of our compounds with PPAR-γ LBD which would allow for structural modifications for improving existing interactions and/or formation of new favorable interactions that could lead to higher affinity and potency. We have also initiated testing of these compounds to determine their PPAR-γ agonistic effects.


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Date of Submission

August 2009