IN SILICO SCREENING OF POTENT PPARGAMMA AGONISTS AMONG NATURAL ANTICANCER COMPOUNDS OF INDIAN ORIGIN
Abstract
ABSTRACT
Objective: Naturally occurring anticancer compounds of Indian origin are well-known for potential therapeutic values. A better understanding of
the intermolecular interactions of these compounds with peroxisome proliferator-activated receptor gamma (PPARγ) is essential, as its activity is
reported in many of the cancers involving colon, breast, gastric, and lung. By this study, it is attempted to perform an in silico screening of natural
anticancer compounds of Indian origin with PPARγ ligand binding domain (LBD). The potential anticancer leads ranked in this study will also exert
an additional advantage of PPARγ activity modulation. As PPARγ is also an important nuclear hormone receptor that modulates transcriptional
regulation of lipid and glucose homeostasis and also a key target for many of the anti-diabetic medications, the compounds ranked by this study will
also be utilized for other related therapeutic effects.
Methods: This study features in silico screening of compounds from Indian Plant Anticancer compounds database against PPARγ LBD main performed
Schrodinger glide virtual screening and docking module to delineate potential PPARγ agonists. Finally, the most potential lead was also subjected to
molecular dynamics simulation to infer the stability of complex formation.
Results: The results reveal that majority of the top ranking compounds that interact with LBD was found to be flavonoids, and all these compounds
were found to interact with key residues involved in PPARγ agonist interactions.
Conclusion: The leads from this study would be helpful in better understanding of the potential of naturally occurring anticancer compounds of
Indian origin toward targeting PPARγ.
Keywords: Peroxisome proliferator-activated receptor-gamma, Agonists, Docking, Natural compounds, Anticancer.
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REFERENCES
Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev
Med 2002;53:409-35.
Boitier E, Gautier JC, Roberts R. Advances in understanding the
regulation of apoptosis and mitosis by peroxisome-proliferator
activated receptors in pre-clinical models: Relevance for human health
and disease. Comp Hepatol 2003;2(1):3.
Yu S, Reddy JK. Transcription coactivators for peroxisome proliferatoractivated
receptors. Biochim Biophys Acta
;1771(8):936-51.
Feige JN, Auwerx J. Transcriptional coregulators in the control of
energy homeostasis. Trends Cell Biol 2007;17(6):292-301.
Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in
fibroblasts by PPAR gamma 2, a lipid-activated transcription factor.
Cell 1994;79(7):1147-56.
Sears IB, MacGinnitie MA, Kovacs LG, Graves RA. Differentiationdependent
expression of the brown adipocyte uncoupling protein gene:
Regulation
by
peroxisome
proliferator-activated
receptor
gamma.
Mol
Cell Biol 1996;16(7):3410-9.
Dussault I, Forman BM. Prostaglandins and fatty acids regulate
transcriptional signaling via the peroxisome proliferator activated
receptor nuclear receptors. Prostaglandins Other Lipid Mediat
;62(1):1-13.
Evans RM, Barish GD, Wang YX. PPARs and the complex journey to
obesity. Nat Med 2004;10(4):355-61.
Heikkinen S, Auwerx J, Argmann CA. PPARgamma in human and
mouse physiology. Biochim Biophys Acta 2007;1771(8):999-1013.
Tontonoz P, Spiegelman BM. Fat and beyond: The diverse biology of
PPAR gamma. Annu Rev Biochem 2008;77:289-312.
Kamijo Y, Nicol CJ, Alexson SE. Pharmacological and toxicological
advances in PPAR-related medicines. PPAR Res 2012;2012:940-64.
Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA,
et al. Loss-of-function mutations in PPAR gamma associated with
human colon cancer. Mol Cell 1999;3(6):799-804.
Perumal PC, Sowmya S, Pratibha P, Vidya B, Anusooriya P, Starlin T,
et al. Identification of novel PPARγ agonist from GC-MS analysis of
ethanolic extract of Cayratia trifolia (L.): A computational molecular
simulation studies. J Appl Pharm Sci 2014;4(09):006-11.
Asian J Pharm Clin Res, Vol 9, Issue 4, 2016, 320-324
Gurula et al.
Weng JR, Chen CY, Pinzone JJ, Ringel MD, Chen CS. Beyond
peroxisome proliferator-activated receptor gamma signaling: The
multi-facets of the antitumor effect of thiazolidinediones. Endocr Relat
Cancer 2006;13(2):401-13.
Sikka S, Chen L, Sethi G, Kumar AP. Targeting PPAR? signaling
cascade for the prevention and treatment of prostate cancer. PPAR Res
;2012:968040.
Pignatelli M, Sánchez-RodrÃguez J, Santos A, Perez-Castillo A
-deoxy-Delta-12,14-prostaglandin J2 induces programmed cell death
of breast cancer cells by a pleiotropic mechanism. Carcinogenesis
;26(1):81-92.
Venkatachalam G, Kumar AP, Sakharkar KR, Thangavel S, Clement MV,
Sakharkar MK. PPAR? Disease gene network and identification of
therapeutic targets for prostate cancer. J Drug Target 2011;19(9):781-96.
Velmurugan P, Kamaraj M, Prema D. Phytochemical constituents of
Cadaba trifoliata Roxb. Root extract. Int J Phytomed 2010;2(4):379-84.
Utsugi T, Shibata J, Sugimoto Y, Aoyagi K, Wierzba K, Kobunai
T, et al. Antitumor activity of a novel podophyllotoxin derivative
(TOP-53) against lung cancer and lung metastatic cancer. Cancer Res
;56(12):2809-14.
Kepler JA, Wani MC, McNaull JN, Wall ME, Levine SG. Plant antitumor
agents. IV. An approach toward the synthesis of camptothecin. J Org
Chem 1969;34(12):3853-8.
Cragg GM, Newman DJ. Plants as a source of anti-cancer agents.
J Ethnopharmacol 2005;100(1-2):72-9.
Johnson IS, Armstrong JG, Gorman M, Burnett JP Jr. The vinca alkaloids:
A new class of oncolytic agents. Cancer Res 1963;23:1390-427.
Arguello F, Alexander M, Sterry JA, Tudor G, Smith EM, Kalavar NT,
et al. Flavopiridol induces apoptosis of normal lymphoid cells,
causes immunosuppression, and has potent antitumor activity In
vivo against human leukemia and lymphoma xenografts. Blood
;91(7):2482-90.
Vetrivel U, Subramanian N, Pilla K. In PACdb – Indian plant anticancer
compounds database. Bioinformation 2009;4(2):71-4.
Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X,
Malainer C, et al. Natural product agonists of peroxisome proliferatoractivated
receptor gamma (PPARγ): A review. Biochem Pharmacol
;92(1):73-89.
Gurula H, Loganathan T, Krishnamoorthy T, Vetrivel U, Samuel S.
Virtual screening studies of seaweed metabolites for predicting
potential PPARγ agonists. Int J Pharm Pharm Sci 2015;7(10):268-71.
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 Deliv Rev
;46(1-3):3-26.
Youssef J, Badr M. Peroxisome proliferator-activated receptors and
cancer: Challenges and opportunities. Br J Pharmacol 2011;164(1):68-82.
Gampe RT Jr, Montana VG, Lambert MH, Miller AB, Bledsoe RK,
Milburn MV, et al. Asymmetry in the PPARgamma/RXRalpha crystal
structure reveals the molecular basis of heterodimerization among
nuclear receptors. Mol Cell 2000;5(3):545-55.
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(5):421-39.
Itoh T, Fairall L, Amin K, Inaba Y, Szanto A, Balint BL, et al. Structural
basis for the activation of PPARgamma by oxidized fatty acids. Nat
Struct Mol Biol 2008;15(9):924-31.
Chen KC, Chen CY. In Silico identification of potent PPAR-? Agonists
from traditional Chinese medicine: A bioactivity prediction, virtual
screening, and molecular dynamics study. Evid Based Complement
Alternat Med 2014;2014:192452.
Saptarini NM, Saputri FA, Levita J. Molecular modeling study of
PPARγ agonists: Dehydro-di-isoeugenol, macelignan, pioglitazone,
netoglitazone, and rosiglitazone as antidiabetic drugs. Int J Chem
;6(2):48.
Miller EG, Peacock JJ, Bourland TC, Taylor SE, Wright JM, Patil BS,
et al. Inhibition of oral carcinogenesis by citrus flavonoids. Nutr Cancer
;60(1):69-74.
López-Lázaro M. Distribution and biological activities of the flavonoid
luteolin. Mini Rev Med Chem 2009;9(1):31-59.
Melstrom LG, Salabat MR, Ding XZ, Milam BM, Strouch M,
Pelling JC, et al. Apigenin inhibits the GLUT-1 glucose transporter and
the phosphoinositide 3-kinase/Akt pathway in human pancreatic cancer
cells. Pancreas 2008;37(4):426-31.
Park JH, Jin CY, Lee BK, Kim GY, Choi YH, Jeong YK. Naringenin
induces apoptosis through downregulation of Akt and caspase-3
activation in human leukemia THP-1 cells. Food Chem Toxicol
;46(12):3684-90.
Privat M, Aubel C, Arnould S, Communal Y, Ferrara M, Bignon YJ.
Breast cancer cell response to genistein is conditioned by BRCA1
mutations. Biochem Biophys Res Commun 2009;379(3):785-9.
Li W, Du B, Wang T, Wang S, Zhang J. Kaempferol induces apoptosis
in human HCT116 colon cancer cells via the Ataxia-telangiectasia
mutated-p53 pathway with the involvement of p53 upregulated
modulator of apoptosis. Chem Biol Interact 2009;177(2):121-7.
Kobori M, Yang Z, Gong D, Heissmeyer V, Zhu H, Jung YK, et al.
Wedelolactone suppresses LPS-induced caspase-11 expression
by directly inhibiting the IKK complex. Cell Death Differ
;11(1):123-30.
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