VIRTUAL SCREENING STUDIES OF SEAWEED METABOLITES FOR PREDICTING POTENTIAL PPARγ AGONISTS
Keywords:
Nil, Agonists, Seaweed, Metabolite, DockingAbstract
Objective: Peroxisome Proliferator-Activated Receptor-gamma (PPARγ) is a crucial nuclear hormone receptor, which modulates the transcriptional regulation of lipid and glucose homeostasis. It plays a crucial role in many of the metabolic and inflammatory systems. It is a key target for many of the anti-diabetic medications. Perturbation of PPARγ activity is also observed in many of the cancers involving colon, breast, gastric and lung. Thus, it is considered to be the hub molecule for targeting many of these cellular disorders. Seaweed metabolites have been well documented to be novel structural entities with a broad spectrum of pharmacological values. However, it is yet to be utilized for screening PPARγ agonists.
Methods: In this study, virtual screening of PPARγ Ligand Binding Domain (LBD) was performed against the datasets from SeaWeed Metabolite Database (SWMD) using Schrodinger Glide High Throughput Virtual Screening module to identify potential PPARγ agonists. Further, the most potential lead was also subjected to molecular dynamics simulation to infer the stability of complex formation.
Results: The results have revealed that bromophenolic compounds from the genus Avrainvillea to interact with documented key residues of LBD involved in agonist interactions. Many other metabolites from the genus Rhodomela, Leathesia, Bifurcaria, Osmundaria, Cymopolia also showed significant interactions with LBD of PPARγ.
Conclusion: The insights from this study will pave the way for further exploration of lead compounds from seaweed metabolites targeting PPARγ.
Â
Â
Downloads
References
Gampe RT Jr, Montana VG, Lambert MH, Miller AB, Bledsoe RK, Milburn MV, et al. Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Molecular Cell 2000;5:545-55.
Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARγ. Annu Rev Biochem 2008;77:289-312.
Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr Rev 1999;20:649-88.
Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53:409-35.
Youssef J, Badr M. Peroxisome proliferator-activated receptors and cancer: challenges and opportunities. Br J Pharmacol 2011;164:68-82.
Lazo JS, Brady LS, Dingledine R. Building a pharmacological lexicon: small molecule discovery in academia. Mol Pharmacol 2007;72:1-7.
Fenical W. Chemical variation in a new bromochamigrene derivative from the red seaweed Laurencia pacifica. Phytochemistry 1976;15:511–2.
Davis GD, Vasanthi AH. Seaweed metabolite database (SWMD): A database of natural compounds from marine algae. Bioinformation 2011;5:361-4.
Selvaa KC, Gadewal NS, Mohammed SM. Identification of leads from marine seaweeds against human β-tubulin. Lett Drug Des Discovery 2013;10:67–74.
Chellasamy S, Mohammed SM. An in silico based comparison of drug interactions in wild and mutant human β-tubulin through docking studies. Avicenna J Med Biotechnol 2014;6:81-93.
Gottlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci USA 1992;89:4653-7.
Amri EZ, Bonino F, Ailhaud G, Abumrad NA, Grimaldi PA. Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J Biol Chem 1995;270:2367-71.
Zoete V, Grosdidier A, Michielin O. Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta 2007;1771:915-25.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 2001;46:3-26.
Lewis SN, Garcia Z, Hontecillas R, Bassaganya-Riera J, Bevan DR. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands. J Comput Aided Mol Des 2015;29:421-39.
Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998;395:137–43.
NyiMekar Saptarini, Febrina Amelia Saputri, Jutti Levita. Molecular modeling study of PPARγ agonists: dehydro-Di-Isoeugenol, Macelignan, Pioglitazone, Netoglitazone, and rosiglitazone as antidiabetic drugs. Int J Chem 2014;6:48.