Lee, Guan Sheng
(2013)
Discovery Of Peroxisome
Proliferator-Activated Receptor
Gamma Agonist.
Masters thesis, Universiti Sains Malaysia.
Abstract
Peroxisome Proliferator- Activator Receptor gamma (PPARγ) is a nuclear
receptor superfamily of ligand activated transcription factor. In biological system,
PPARγ plays a crucial role in regulating glucose and lipid metabolism. For that reason,
PPARγ has drawn enormous attention as a potential target for designing novel drug to
treat type-2- diabetes. PPARγ agonist, Rosiglitazone, is the first line drug for improving
insulin sensitivity of type 2 diabetes. However, recent studies indicated that
Rosiglitazone are causing undesired side effects like weight gain, oedema and fluid
retention. Thus, it is necessary to search for PPARγ agonist for a less complication
alternative. In this study, virtual screening using molecular docking approach was done
against 5000 compounds; 3000 compounds were from Nature-Based Drug Discovery
(NADI®) Database and another 2000 compounds were taken from National Cancer
Institute (NCI) Diversity Set 1 library. The top 100 hits with lowest free energy of
binding were further analyzed based on their favorable binding mode. A total of four
compounds were selected from NCI library and two plants (Temu kunci and Ketumbar)
were selected from Malaysia natural resources to test against PPARγ in vitro. From the
assay result, the most active compounds from NCI database were NCI37245, which
activated PPARγ at EC50 of 43.6nM.While for the selected plants, the methanol crude
extracts of Temu kunci was more active compared with Ketumbar. The crude extracts of
Temu kunci activate PPARγ at about 1.5 fold higher compared with Ketumbar (1.6 fold)
with the EC50 of 50.0ng/mL.
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