Main Area of Interest
Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The PPAR isoforms (α, β & γ) are known to control many physiological functions including glucose absorption, lipid homeostasis and cell growth & differentiation. Of particular interest, agonist modulation of PPARγ was shown to mitigate the inflammatory responses associated with chronic and acute neurological insults. On the basis of these investigations, drug design towards PPARγ modulators has been highlighted as a plausible approach for treatment of a wide range of neuropathological disorders (Alzheimer’s disease, Multiple Sclerosis and Parkinson’s disease).
The main focus of my work is the development of novel agonist modulators of PPARγ activity. This will be achieved through the implementation of a customised virtual screening protocol for PPARγ. An array of Structure-Based and Ligand-Based Drug Design methodologies will be employed for the identification of putative small molecule agonists of PPARγ.
Subsequent to computational screening against the target of interest, any potential drug candidate will be brought through initial "proof of concept" experimentation. This will include on-target assays implementing Fluorescent Polarisation (FP) and Time Resolved – Fluorescent Resonance Energy Transfer (TR-FRET) biochemical techniques and in vitro testing on established cellular models of different neuropathological disease states. If candidate compounds successfully pass this crucial development step, it is hoped that their activities will be studied in in vivo animal models of same.
At each project step, the experimental approach will be iterative with a view to developing the most plausible drug- like candidate for use in the treatment of the neuropathologies of interest. Also, the design avenues of partial PPARγ and dual α/γ agonism will also be explored as rational approaches to drug discovery for the attenuation of neuroinflammation in the disease state.
History:
B.A. Mod. (TCD '07)Graduate Student (Sept 2009-Current)
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