Abstract
Metabolic syndrome is characterized by the clustering of abnormalities such as high blood pressure, low HDL, high LDL, central obesity and raised fasting blood glucose. These abnormalities increase the risk of developing cardiovascular disease and diabetes. The nuclear receptor, peroxisome proliferator activated receptor delta (PPARδ), also known as NR1C2, is known to regulate lipid metabolism. It is modulated by ligand binding. In this study, we have used molecular docking technique to find a candidate agonist for PPARδ. Docking study was performed with 346 compounds (obtained from PubChem) similar to GW501516 and the molecular target PPARδ (crystallographic structure was obtained from RSCB database) using AutoDock Vina 4.2 and ADT 1.5.4 program. The docked ligands were analyzed on the basis of binding free energy and hydrogen bond interactions. The docked ligands showed favourable hydrogen bonding with the receptor at a distance of 3.7 Å. Among the compounds analyzed, two ligands were considered, namely, ethyl-2-[2-methyl-4-[1-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]-5-phenylpentyl]sulfanylphenoxy] acetate with a binding free energy of −11.0 kcal/mol and zero hydrogen bonds and ethyl-2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]-(2,3,4,5,6-pentafluorophenyl)methyl]sulfanylphenoxy] acetate with binding free energy of −10.4 kcal/mol and two hydrogen bonds with Glu 471 of the B chain and Asn 312 of the A chain of the receptor. Further wet lab studies need to be carried out to study the functional characteristics of the ligands on PPARδ and its role in the syndrome.
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Acknowledgement
Serena D’Souza would like to thank CSIR for providing Junior Research Fellowship to pursue doctoral studies. Dr. Asha Abraham would like to thank UGC for providing a major research project. All the authors thank the Principal, St. Aloysius College and Director, AIMIT for providing support and necessary facilities to carry out this work.
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D’Souza, S., Maheshwari, U., Rebello, S., Abraham, A. (2012). Identification of a PPAR Delta Agonist: An In Silico Approach Towards Drug Design for Metabolic Syndrome. In: Sabu, A., Augustine, A. (eds) Prospects in Bioscience: Addressing the Issues. Springer, India. https://doi.org/10.1007/978-81-322-0810-5_9
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DOI: https://doi.org/10.1007/978-81-322-0810-5_9
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