Comparative Computational Screening of Natural-based Partial Agonists
for PPARγ Receptor

Leila      Moradihaghgou; Reinhard      Schneider; Bahram   Maleki   Zanjani; Taher      Harkinezhad
doi:10.2174/1573406419666230103142021
Abstract

Introduction: The nuclear transcription factor PPARγ, which can modulate cell growth via proliferation and apoptosis-related mechanisms, is a promising target in cancer therapy. This study aims to focus on PPARγ as the target and use virtual screening to find hits.
Methods: A set of 5,677 flavonoid compounds were filtered by subjecting them to descriptor-based drug-likeness and ADMET strategies to discover drug-like compounds. The candidates' modes of binding to PPARγ were then evaluated using docking and MD simulation. PharmMapper was used to identify the potential targets of selected hits. The pharmacological network was constructed based on the GO and KEGG pathway analysis.
Results: In primary screening, 3,057 compounds met various drug-likeness criteria and docked well as partial agonists in the PPARγ-LBD. Five compounds (euchrenone b₁, kaempferol-7-Orhamnoside, vincetoxicoside B, morusin, and karanjin) were selected with the use of ADMET profiles for further MD simulation investigation. Based on the PharmMapper findings, 52 proteins were then submitted to GO and KEGG enrichment analysis. As expected by GO and KEGG pathway enrichment studies, core targets were enriched in the PI3K-Akt signaling pathway (p < 0.01), indicating that certain chemicals may be involved in cancer processes.
Conclusion: Our results suggested that the selected compounds might have sufficient drug-likeness, pharmacokinetics, and in silico bioactivity by acting as PPARγ partial agonists. Although much work remains to illuminate extensive cancer therapeutic/ chemopreventive efficacy of flavonoids in vivo, in silico methodology of our cheminformatics research may be able to provide additional data regarding the efficacy and safety of potential candidates for therapeutic targets.
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[1]
Ghavami, G.; Sardari, S.; Shokrgozar, M.A. Anticancerous potentials of Achillea species against selected cell lines. J. Med. Plants Res.,  2010, 4(22), 2411-2417.

[2]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin.,  2018, 68(6), 394-424.
 [http://dx.doi.org/10.3322/caac.21492] [PMID:  30207593]

[3]
Youssef, J.; Badr, M. Peroxisome proliferator-activated receptors and cancer: challenges and opportunities. Br. J. Pharmacol.,  2011, 164(1), 68-82.
 [http://dx.doi.org/10.1111/j.1476-5381.2011.01383.x] [PMID:  21449912]

[4]
Wang, L.; Waltenberger, B.; Pferschy-Wenzig, E.M.; Blunder, M.; Liu, X.; Malainer, C.; Blazevic, T.; Schwaiger, S.; Rollinger, J.M.; Heiss, E.H.; Schuster, D.; Kopp, B.; Bauer, R.; Stuppner, H.; Dirsch, V.M.; Atanasov, A.G. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochem. Pharmacol.,  2014, 92(1), 73-89.
 [http://dx.doi.org/10.1016/j.bcp.2014.07.018] [PMID:  25083916]

[5]
Kaserer, T.; Obermoser, V.; Weninger, A.; Gust, R.; Schuster, D. Evaluation of selected 3D virtual screening tools for the prospective identification of peroxisome proliferator-activated receptor (PPAR) γ partial agonists. Eur. J. Med. Chem.,  2016, 124, 49-62.
 [http://dx.doi.org/10.1016/j.ejmech.2016.07.072] [PMID:  27560282]

[6]
Zoete, V.; Grosdidier, A.; Michielin, O. Peroxisome proliferator-activated receptor structures: Ligand specificity, molecular switch and interactions with regulators. Biochim. Biophys. Acta Mol. Cell Biol. Lipids,  2007, 1771(8), 915-925.
 [http://dx.doi.org/10.1016/j.bbalip.2007.01.007] [PMID:  17317294]

[7]
Vella, V.; Nicolosi, M.L.; Giuliano, S.; Bellomo, M.; Belfiore, A.; Malaguarnera, R. PPAR-γ agonists as antineoplastic agents in cancers with dysregulated IGF axis. Front. Endocrinol.,  2017, 8, 31.
 [http://dx.doi.org/10.3389/fendo.2017.00031] [PMID:  28275367]

[8]
Nagata, D.; Yoshihiro, H.; Nakanishi, M.; Naruyama, H.; Okada, S.; Ando, R.; Tozawa, K.; Kohri, K. Peroxisome proliferator-activated receptor-γ and growth inhibition by its ligands in prostate cancer. Cancer Detect. Prev.,  2008, 32(3), 259-266.
 [http://dx.doi.org/10.1016/j.cdp.2008.05.008] [PMID:  18789607]

[9]
Rasouli, H.; Farzaei, M.H.; Khodarahmi, R. Polyphenols and their benefits: A review. Int. J. Food Properties,,  2017, 20(s2), 1700-1741.
 [http://dx.doi.org/10.1080/10942912.2017.1354017]

[10]
Shahidi, F.; Yeo, J. Bioactivities of phenolics by focusing on suppression of chronic diseases: a review. Int. J. Mol. Sci.,  2018, 19(6), 1573.
 [http://dx.doi.org/10.3390/ijms19061573] [PMID:  29799460]

[11]
Oliveira, L.L.; Carvalho, M.V.; Melo, L. Health promoting and sensory properties of phenolic compounds in food. Rev. Ceres,  2014, 61, 764-779.
 [http://dx.doi.org/10.1590/0034-737x201461000002]

[12]
Kim, H.P.; Son, K.H.; Chang, H.W.; Kang, S.S. Anti-inflammatory plant flavonoids and cellular action mechanisms. J. Pharmacol. Sci.,  2004, 96(3), 229-245.
 [http://dx.doi.org/10.1254/jphs.CRJ04003X] [PMID:  15539763]

[13]
Rasouli, H.; Mazinani, M.H.; Haghbeen, K. Benefits and challenges of olive biophenols: a perspective. Olives and Olive Oil in Health and Disease Prevention; Elsevier, 2021, pp. 489-503.
 [http://dx.doi.org/10.1016/B978-0-12-819528-4.00045-6]

[14]
Rodríguez, M.L.; Estrela, J.M.; Ortega, Á Natural polyphenols and apoptosis induction in cancer therapy. J. Carcinog Mutag S,,  2013, 6.

[15]
Stein, M.L.; Groll, M. Applied techniques for mining natural proteasome inhibitors. Biochimica et Biophysica Acta (BBA)-. Mol. Cell Res.,  2014, 1843(1), 26-38.

[16]
Rasouli, H.; Farzaei, M.; Mansouri, K.; Mohammadzadeh, S.; Khodarahmi, R. Plant cell cancer: may natural phenolic compounds prevent onset and development of plant cell malignancy? A literature review. Molecules,  2016, 21(9), 1104.
 [http://dx.doi.org/10.3390/molecules21091104] [PMID:  27563858]

[17]
Mihaleva, V.V.; te Beek, T.A.H.; van Zimmeren, F.; Moco, S.; Laatikainen, R.; Niemitz, M.; Korhonen, S.P.; van Driel, M.A.; Vervoort, J. MetIDB: a publicly accessible database of predicted and experimental 1H NMR spectra of flavonoids. Anal. Chem.,  2013, 85(18), 8700-8707.
 [http://dx.doi.org/10.1021/ac4016837] [PMID:  23930710]

[18]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform.,  2011, 3(1), 33.
 [http://dx.doi.org/10.1186/1758-2946-3-33] [PMID:  21982300]

[19]
Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform.,  2012, 4(1), 17.
 [http://dx.doi.org/10.1186/1758-2946-4-17] [PMID:  22889332]

[20]
Pires, D.E.V.; Blundell, T.L.; Ascher, D.B. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem.,  2015, 58(9), 4066-4072.
 [http://dx.doi.org/10.1021/acs.jmedchem.5b00104] [PMID:  25860834]

[21]
Banerjee, P.; Eckert, A.O.; Schrey, A.K.; Preissner, R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res.,  2018, 46(W1), W257-W263.
 [http://dx.doi.org/10.1093/nar/gky318] [PMID:  29718510]

[22]
Dong, J.; Wang, N.N.; Yao, Z.J.; Zhang, L.; Cheng, Y.; Ouyang, D.; Lu, A.P.; Cao, D.S. ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. J. Cheminform.,  2018, 10(1), 29.
 [http://dx.doi.org/10.1186/s13321-018-0283-x] [PMID:  29943074]

[23]
Xu, Y.; Wang, S.; Hu, Q.; Gao, S.; Ma, X.; Zhang, W.; Shen, Y.; Chen, F.; Lai, L.; Pei, J. CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction. Nucleic Acids Res.,  2018, 46(W1), W374-W379.
 [http://dx.doi.org/10.1093/nar/gky380] [PMID:  29750256]

[24]
Tian, W.; Chen, C.; Lei, X.; Zhao, J.; Liang, J. CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Res.,  2018, 46(W1), W363-W367.
 [http://dx.doi.org/10.1093/nar/gky473] [PMID:  29860391]

[25]
Wakabayashi, K.; Hayashi, S.; Matsui, Y.; Matsumoto, T.; Furukawa, A.; Kuroha, M.; Tanaka, N.; Inaba, T.; Kanda, S.; Tanaka, J.; Okuyama, R.; Wakimoto, S.; Ogata, T.; Araki, K.; Ohsumi, J. Pharmacology and in vitro profiling of a novel peroxisome proliferator-activated receptor γ ligand, Cerco-A. Biol. Pharm. Bull.,  2011, 34(7), 1094-1104.
 [http://dx.doi.org/10.1248/bpb.34.1094] [PMID:  21720019]

[26]
Eswar, N.; Webb, B. Marti‐Renom, M.A.; Madhusudhan, M.; Eramian, D.; Shen, M.; Pieper, U.; Sali, A. Comparative protein structure modeling using modeller. Curr. Protoc. Protein Sci.,  2007, 15(1), 5-6.
 [http://dx.doi.org/10.1002/0471140864.ps0209s50]

[27]
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. Chemical Biology; Springer, 2015, pp. 243-250.

[28]
Hsu, K.C.; Chen, Y.F.; Lin, S.R.; Yang, J.M. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics,  2011, 12(S1)(Suppl. 1), S33.
 [http://dx.doi.org/10.1186/1471-2105-12-S1-S33] [PMID:  21342564]

[29]
Rasouli, H.; Hosseini Ghazvini, S.M.B.; Yarani, R. Altıntaş, A.; Jooneghani, S.G.N.; Ramalho, T.C. Deciphering inhibitory activity of flavonoids against tau protein kinases: a coupled molecular docking and quantum chemical study. J. Biomol. Struct. Dyn.,  2020, 40(1), 1-14.
 [PMID:  32897165]

[30]
Rasouli, H.; Hosseini-Ghazvini, S.M.B.; Adibi, H.; Khodarahmi, R. Differential α-amylase/α-glucosidase inhibitory activities of plant-derived phenolic compounds: a virtual screening perspective for the treatment of obesity and diabetes. Food Funct.,  2017, 8(5), 1942-1954.
 [http://dx.doi.org/10.1039/C7FO00220C] [PMID:  28470323]

[31]
Guasch, L.; Sala, E. Castell-Auví; A.; Cedó, L.; Liedl, K.R.; Wolber, G.; Muehlbacher, M.; Mulero, M.; Pinent, M.; Ardévol, A.; Valls, C.; Pujadas, G.; Garcia-Vallvé, S. Identification of PPARgamma partial agonists of natural origin (I): development of a virtual screening procedure and in vitro validation. PLoS One,  2012, 7(11), e50816.
 [http://dx.doi.org/10.1371/journal.pone.0050816] [PMID:  23226391]

[32]
Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I.; Mackerell, A.D. Jr CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem.,  2010, 31(4), 671-690.
 [PMID:  19575467]

[33]
Basith, S.; Manavalan, B.; Shin, T.; Lee, G. A molecular dynamics approach to explore the intramolecular signal transduction of PPAR--α. Int. J. Mol. Sci.,  2019, 20(7), 1666.
 [http://dx.doi.org/10.3390/ijms20071666] [PMID:  30987171]

[34]
Khan, T.; Dixit, S.; Ahmad, R.; Raza, S.; Azad, I.; Joshi, S.; Khan, A.R. Molecular docking, PASS analysis, bioactivity score prediction, synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes. J. Chem. Biol.,  2017, 10(3), 91-104.
 [http://dx.doi.org/10.1007/s12154-017-0167-y] [PMID:  28684996]

[35]
Wang, X.; Shen, Y.; Wang, S.; Li, S.; Zhang, W.; Liu, X.; Lai, L.; Pei, J.; Li, H. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res.,  2017, 45(W1), W356-W360.
 [http://dx.doi.org/10.1093/nar/gkx374] [PMID:  28472422]

[36]
Zhang, J.; Xie, Y.; Fan, Q.; Wang, C. Effects of karanjin on dimethylhydrazine induced colon carcinoma and aberrant crypt foci are facilitated by alteration of the p53/Bcl2/BAX pathway for apoptosis. Biotech. Histochem.,  2021, 96(3), 202-212.
 [http://dx.doi.org/10.1080/10520295.2020.1781258] [PMID:  32580584]

[37]
Garcia-Sosa, A.T.; Maran, U.; Hetenyi, C. Molecular property filters describing pharmacokinetics and drug binding. Curr. Med. Chem.,  2012, 19(11), 1646-1662.
 [http://dx.doi.org/10.2174/092986712799945021] [PMID:  22376034]

[38]
Ursu, O.; Rayan, A.; Goldblum, A.; Oprea, T.I. Understanding drug-likeness. Wiley Interdiscip. Rev. Comput. Mol. Sci.,  2011, 1(5), 760-781.
 [http://dx.doi.org/10.1002/wcms.52]

[39]
Hosseini Ghazvini, S.M.B.; Safari, P.; Mobinikhaledi, A.; Moghanian, H.; Rasouli, H. Synthesis, characterization, anti-diabetic potential and DFT studies of 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde oxime. Spectrochim. Acta A Mol. Biomol. Spectrosc.,  2018, 205, 111-131.
 [http://dx.doi.org/10.1016/j.saa.2018.07.009] [PMID:  30015017]

[40]
Pascolutti, M.; Quinn, R.J. Natural products as lead structures: chemical transformations to create lead-like libraries. Drug Discov. Today,  2014, 19(3), 215-221.
 [http://dx.doi.org/10.1016/j.drudis.2013.10.013] [PMID:  24171951]

[41]
Guan, L.; Yang, H.; Cai, Y.; Sun, L.; Di, P.; Li, W.; Liu, G.; Tang, Y. ADMET-score – a comprehensive scoring function for evaluation of chemical drug-likeness. MedChemComm,  2019, 10(1), 148-157.
 [http://dx.doi.org/10.1039/C8MD00472B] [PMID:  30774861]

[42]
Lagorce, D.; Douguet, D.; Miteva, M.A.; Villoutreix, B.O. Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors. Sci. Rep.,  2017, 7(1), 46277.
 [http://dx.doi.org/10.1038/srep46277] [PMID:  28397808]

[43]
Chung, F.S.; Santiago, J.S.; Jesus, M.F.; Trinidad, C.V.; See, M.F.E. Disrupting P-glycoprotein function in clinical settings: what can we learn from the fundamental aspects of this transporter? Am. J. Cancer Res.,  2016, 6(8), 1583-1598.
 [PMID:  27648351]

[44]
Sharma, K.; Mishra, K.; Senapati, K.K.; Danciu, C. Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health; BoD–Books on Demand, 2021. 
 [http://dx.doi.org/10.5772/intechopen.78846]

[45]
Zhou, S.F. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr. Drug Metab.,  2008, 9(4), 310-322.
 [http://dx.doi.org/10.2174/138920008784220664] [PMID:  18473749]

[46]
Calderón-Montaño, J.M.; Burgos-Morón, E.; Pérez-Guerrero, C.; López-Lázaro, M. A review on the dietary flavonoid kaempferol. Mini Rev. Med. Chem.,  2011, 11(4), 298-344.
 [http://dx.doi.org/10.2174/138955711795305335] [PMID:  21428901]

[47]
Batra, P.; Sharma, A. K. Anti-cancer potential of flavonoids: recent trends and future perspectives. 3 Biotech,,  2013, 3(6), 439-459.

[48]
Iheagwam, F.N.; Ogunlana, O.O.; Ogunlana, O.E.; Isewon, I.; Oyelade, J. Potential anti-cancer flavonoids isolated from Caesalpinia bonduc young twigs and leaves: molecular docking and in silico studies. Bioinform. Biol. Insights,  2019, 13
 [http://dx.doi.org/10.1177/1177932218821371] [PMID:  30670919]

[49]
Zanger, U.M.; Schwab, M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther.,  2013, 138(1), 103-141.
 [http://dx.doi.org/10.1016/j.pharmthera.2012.12.007] [PMID:  23333322]

[50]
Shi, X.; Yang, S.; Zhang, G.; Song, Y.; Su, D.; Liu, Y.; Guo, F.; Shan, L.; Cai, J. The different metabolism of morusin in various species and its potent inhibition against UDP-glucuronosyl-transferase (UGT) and cytochrome p450 (CYP450) enzymes. Xenobiotica,  2016, 46(5), 467-476.
 [http://dx.doi.org/10.3109/00498254.2015.1086839] [PMID:  26372370]

[51]
Jung, H.; Lee, S. Inhibition of human cytochrome P450 enzymes by allergen removed Rhus verniciflua stoke standardized extract and constituents. Evid.-based Complement. Altern. Med. eCAM,  2014, 2014, 1-5.

[52]
Wang, H.J.; Pao, L.H.; Hsiong, C.H.; Shih, T.Y.; Lee, M.S.; Hu, O.Y.P. Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship. AAPS J.,  2014, 16(2), 258-268.
 [http://dx.doi.org/10.1208/s12248-013-9549-4] [PMID:  24431079]

[53]
Wang, X.; Yu, T.; Liao, X.; Yang, C.; Han, C.; Zhu, G.; Huang, K.; Yu, L.; Qin, W.; Su, H.; Liu, X.; Peng, T. The prognostic value of CYP2C subfamily genes in hepatocellular carcinoma. Cancer Med.,  2018, 7(4), 966-980.
 [http://dx.doi.org/10.1002/cam4.1299] [PMID:  29479826]

[54]
Androutsopoulos, V.P.; Papakyriakou, A.; Vourloumis, D.; Tsatsakis, A.M.; Spandidos, D.A. Dietary flavonoids in cancer therapy and prevention: Substrates and inhibitors of cytochrome P450 CYP1 enzymes. Pharmacol. Ther.,  2010, 126(1), 9-20.
 [http://dx.doi.org/10.1016/j.pharmthera.2010.01.009] [PMID:  20153368]

[55]
Zhang, F.; Yuan, Y.; Wang, J.; Li, Z.; Cui, S.; Zhu, F.; Qiu, D.; Wang, Y.; Li, R. Characterization of metabolism feature and potential pharmacological changes of morusin-a promising anti-tumor drug-by ultra-high-performance liquid chromatography coupled time-of-flight mass spectrometry and network pharmacology. Arab. J. Chem.,  2021, 14(2), 102964.
 [http://dx.doi.org/10.1016/j.arabjc.2020.102964]

[56]
Shejawal, N.; Menon, S.; Shailajan, S. Bioavailability of karanjin from Pongamia pinnata L. in Sprague dawley rats using validated RP-HPLC method. J. Appl. Pharm. Sci.,  2014, 4(3), 10-14.

[57]
Pang, Q.; Tian, Y.; Mi, J.; Wang, J.; Xu, Y. Simultaneous determination and pharmacokinetic study of eight components in rat plasma by UHPLC-MS/MS after oral administration of Hypericum japonicum Thunb extract. J. Pharm. Biomed. Anal.,  2016, 118, 228-234.
 [http://dx.doi.org/10.1016/j.jpba.2015.10.027] [PMID:  26580819]

[58]
Chen, M.; Suzuki, A.; Borlak, J.; Andrade, R.J.; Lucena, M.I. Drug-induced liver injury: Interactions between drug properties and host factors. J. Hepatol.,  2015, 63(2), 503-514.
 [http://dx.doi.org/10.1016/j.jhep.2015.04.016] [PMID:  25912521]

[59]
Joshi, P.; Sonawane, V.R.; Williams, I.S.; McCann, G.J.P.; Gatchie, L.; Sharma, R.; Satti, N.; Chaudhuri, B.; Bharate, S.B. Identification of karanjin isolated from the Indian beech tree as a potent CYP1 enzyme inhibitor with cellular efficacy via screening of a natural product repository. MedChemComm,  2018, 9(2), 371-382.
 [http://dx.doi.org/10.1039/C7MD00388A] [PMID:  30108931]

[60]
Macgregor, J.T.; Jurd, L. Mutagenicity of plant flavonoids: Structural requirements for mutagenic activity in Salmonella typhimurium. Mutat. Res. Envir. Mutag. Relat. Subj.,  1978, 54(3), 297-309.
 [http://dx.doi.org/10.1016/0165-1161(78)90020-1] [PMID:  368618]

[61]
Amjad, E.; Sokouti, B.; Asnaashari, S. A systematic review of anti-cancer roles and mechanisms of kaempferol as a natural compound. Cancer Cell Int.,  2022, 22(1), 260.
 [http://dx.doi.org/10.1186/s12935-022-02673-0] [PMID:  35986346]

[62]
Alam, W.; Khan, H.; Shah, M.A.; Cauli, O.; Saso, L. Kaempferol as a dietary anti-inflammatory agent: Current therapeutic standing. Molecules,  2020, 25(18), 4073.
 [http://dx.doi.org/10.3390/molecules25184073] [PMID:  32906577]

[63]
Amawi, H.; Ashby, C.R., Jr; Tiwari, A.K. Cancer chemoprevention through dietary flavonoids: what’s limiting? Chin. J. Cancer,  2017, 36(1), 50.
 [http://dx.doi.org/10.1186/s40880-017-0217-4] [PMID:  28061892]

[64]
Xue, J.; Li, R.; Zhao, X.; Ma, C.; Lv, X.; Liu, L.; Liu, P. Morusin induces paraptosis-like cell death through mitochondrial calcium overload and dysfunction in epithelial ovarian cancer. Chem. Biol. Interact.,  2018, 283, 59-74.
 [http://dx.doi.org/10.1016/j.cbi.2018.02.003] [PMID:  29421517]

[65]
Nguyen, T.P.; Tran, C.L.; Vuong, C.H.; Do, T.H.T.; Le, T.D.; Mai, D.T.; Phan, N.M. Flavonoids with hepatoprotective activity from the leaves of Cleome viscosa L. Nat. Prod. Res.,  2017, 31(22), 2587-2592.
 [http://dx.doi.org/10.1080/14786419.2017.1283497] [PMID:  28135851]

[66]
Chan, E.W.C.; Wong, S.K.; Tangah, J.; Inoue, T.; Chan, H.T. Phenolic constituents and anticancer properties of Morus alba (white mulberry) leaves. J. Integr. Med.,  2020, 18(3), 189-195.
 [http://dx.doi.org/10.1016/j.joim.2020.02.006] [PMID:  32115383]

[67]
Li, X.; Wang, D.; Xia, M.; Wang, Z.; Wang, W.; Cui, Z. Cytotoxic prenylated flavonoids from the stem bark of Maackia amurensis. Chem. Pharm. Bull.,  2009, 57(3), 302-306.
 [http://dx.doi.org/10.1248/cpb.57.302] [PMID:  19252325]

[68]
Belagihally, S.M.; Rajashekhar, S.; Jayaram, V.B.; Dharmesh, S.M.; Thirumakudalu, S.K.C. Gastroprotective properties of karanjin from Karanja (Pongamia pinnata) seeds; Role as antioxidant and H+, K+-ATPase inhibitor. Evid.-based Complement. Altern. Med. eCAM,,  2011, 2011, 747246.

[69]
Singh, S.; Mohanty, A. In silico identification of potential drug compound against Peroxisome proliferator-activated receptor-gamma by virtual screening and toxicity studies for the treatment of diabetic nephropathy. J. Biomol. Struct. Dyn.,  2018, 36(7), 1776-1787.
 [http://dx.doi.org/10.1080/07391102.2017.1334596] [PMID:  28539091]

[70]
Jang, J.Y.; Bae, H.; Lee, Y.J.; Choi, Y.I.; Kim, H.J.; Park, S.B.; Suh, S.W.; Kim, S.W.; Han, B.W. Structural basis for the enhanced anti-diabetic efficacy of lobeglitazone on PPARγ. Sci. Rep.,  2018, 8(1), 31.
 [http://dx.doi.org/10.1038/s41598-017-18274-1] [PMID:  29311619]

[71]
Petrosino, M.; Lori, L.; Pasquo, A.; Lori, C.; Consalvi, V.; Minicozzi, V.; Morante, S.; Laghezza, A.; Giorgi, A.; Capelli, D.; Chiaraluce, R. Single-nucleotide polymorphism of PPARγ a protein at the crossroads of physiological and pathological processes. Int. J. Mol. Sci.,  2017, 18(2), 361.
 [http://dx.doi.org/10.3390/ijms18020361] [PMID:  28208577]

[72]
Kroker, A. J.; Bruning, J. B. Review of the structural and dynamic mechanisms of PPARγ partial agonism. PPAR Res.,,  2015, 2015

[73]
Lee, M.A.; Tan, L.; Yang, H. Im, Y-G.; Im, Y.J. Structures of PPARγ complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs. Sci. Rep.,  2017, 7(1), 16837.
 [http://dx.doi.org/10.1038/s41598-017-17082-x] [PMID:  28127051]

[74]
Lemkul, J.A.; Lewis, S.N.; Bassaganya-Riera, J.; Bevan, D.R. Phosphorylation of PPARγ affects the collective motions of the PPARγ-RXRα-DNA complex. PLoS One,  2015, 10(5), e0123984.
 [http://dx.doi.org/10.1371/journal.pone.0123984] [PMID:  25954810]

[75]
Muralikumar, S.; Vetrivel, U.; Narayanasamy, A.; Das, U.N. Probing the intermolecular interactions of PPARγ-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties. Lipids Health Dis.,  2017, 16(1), 1-11.
 [http://dx.doi.org/10.1186/s12944-016-0404-3] [PMID:  28056980]

[76]
Mallick, B. Molecular dynamics simulations reveal the role of ceramicine B as novel PPARγ partial agonist against type 2 diabetes.,  2018, 1808.08375.

[77]
Lemmon, G.; Meiler, J. Towards ligand docking including explicit interface water molecules. PLoS One,  2013, 8(6), e67536.
 [http://dx.doi.org/10.1371/journal.pone.0067536] [PMID:  23840735]

[78]
Huber, R.G.; Margreiter, M.A.; Fuchs, J.E.; von Grafenstein, S.; Tautermann, C.S.; Liedl, K.R.; Fox, T. Heteroaromatic π--stacking energy landscapes. J. Chem. Inf. Model.,  2014, 54(5), 1371-1379.
 [http://dx.doi.org/10.1021/ci500183u] [PMID:  24773380]

[79]
Chen, R.; Wan, J.; Song, J.; Qian, Y.; Liu, Y.; Gu, S. Rational screening of peroxisome proliferator-activated receptor-γ agonists from natural products: potential therapeutics for heart failure. Pharm. Biol.,  2017, 55(1), 503-509.
 [http://dx.doi.org/10.1080/13880209.2016.1255648] [PMID:  27937122]

[80]
Mazumder, M.; Ponnan, P.; Das, U.; Gourinath, S.; Khan, H.A.; Yang, J.; Sakharkar, M.K. Investigations on binding pattern of kinase inhibitors with PPARγ molecular docking, molecular dynamic simulations, and free energy calculation studies. PPAR Res.,  2017, 2017, 6397836.

[81]
Huang, H.; Zhang, G.; Zhou, Y.; Lin, C.; Chen, S.; Lin, Y.; Mai, S.; Huang, Z. Reverse screening methods to search for the protein targets of chemopreventive compounds. Front Chem.,  2018, 6, 138.
 [http://dx.doi.org/10.3389/fchem.2018.00138] [PMID:  29868550]

[82]
Liu, X.; Ouyang, S.; Yu, B.; Liu, Y.; Huang, K.; Gong, J.; Zheng, S.; Li, Z.; Li, H.; Jiang, H. PharmMapper server: a web server for potential drug target identification using pharmacophore mapping approach. Nucleic Acids Res.,,  2010, 38 (Web Server issue)(Suppl. 2), W609-W614
 [http://dx.doi.org/10.1093/nar/gkq300] [PMID: 20430828]

[83]
Choi, D.W.; Cho, S.W.; Lee, S.G.; Choi, C.Y. The beneficial effects of Morusin, an isoprene flavonoid isolated from the root bark of Morus. Int. J. Mol. Sci.,  2020, 21(18), 6541.
 [http://dx.doi.org/10.3390/ijms21186541] [PMID:  32906784]

[84]
Lee, J.C.; Won, S.J.; Chao, C.L.; Wu, F.L.; Liu, H.S.; Ling, P.; Lin, C.N.; Su, C.L. Morusin induces apoptosis and suppresses NF-κB activity in human colorectal cancer HT-29 cells. Biochem. Biophys. Res. Commun.,  2008, 372(1), 236-242.
 [http://dx.doi.org/10.1016/j.bbrc.2008.05.023] [PMID:  18485277]

[85]
Wang, J.; Liu, X.; Zheng, H.; Liu, Q.; Zhang, H.; Wang, X.; Shen, T.; Wang, S.; Ren, D. Morusin induces apoptosis and autophagy via JNK, ERK and PI3K/Akt signaling in human lung carcinoma cells. Chem. Biol. Interact.,  2020, 331, 109279.
 [http://dx.doi.org/10.1016/j.cbi.2020.109279] [PMID:  33035517]

[86]
Cho, A.R.; Park, W.Y.; Lee, H.J.; Sim, D.Y.; Im, E.; Park, J.E.; Ahn, C.H.; Shim, B.S.; Kim, S.H. Antitumor effect of morusin via G1 arrest and antiglycolysis by AMPK activation in hepatocellular cancer. Int. J. Mol. Sci.,  2021, 22(19), 10619.
 [http://dx.doi.org/10.3390/ijms221910619] [PMID:  34638959]

[87]
Cho, S.W.; Na, W.; Choi, M.; Kang, S.J.; Lee, S-G.; Choi, C.Y. Autophagy inhibits cell death induced by the anti-cancer drug morusin. Am. J. Cancer Res.,  2017, 7(3), 518-530.
 [PMID:  28401008]

[88]
Bhatt, G.; Gupta, A.; Rangan, L.; Mukund Limaye, A. Global transcriptome analysis reveals partial estrogen-like effects of karanjin in MCF-7 breast cancer cells. Gene,  2022, 830, 146507.
 [http://dx.doi.org/10.1016/j.gene.2022.146507] [PMID:  35447244]

[89]
Guo, J.R.; Chen, Q.Q.; Lam, C.W.K.; Zhang, W. Effects of karanjin on cell cycle arrest and apoptosis in human A549, HepG2 and HL-60 cancer cells. Biol. Res.,  2015, 48(1), 40.
 [http://dx.doi.org/10.1186/s40659-015-0031-x] [PMID:  26209237]

[90]
Roy, R.; Pal, D.; Sur, S.; Mandal, S.; Saha, P.; Panda, C.K. Pongapin and Karanjin, furanoflavanoids of PONGAMIA PINNATA, induce G2/M arrest and apoptosis in cervical cancer cells by differential reactive oxygen species modulation, DNA damage, and nuclear factor kappa‐light‐chain‐enhancer of activated B cell signaling. Phytother. Res.,  2019, 33(4), 1084-1094.
 [http://dx.doi.org/10.1002/ptr.6302] [PMID:  30834631]

[91]
Jaiswal, N.; Yadav, P.P.; Maurya, R.; Srivastava, A.K.; Tamrakar, A.K. Karanjin from Pongamia pinnata induces GLUT4 translocation in skeletal muscle cells in a phosphatidylinositol-3-kinase-independent manner. Eur. J. Pharmacol.,  2011, 670(1), 22-28.
 [http://dx.doi.org/10.1016/j.ejphar.2011.08.049] [PMID:  21939653]

[92]
Liu, C.; Seeram, N.P.; Ma, H. Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review. Cancer Cell Int.,  2021, 21(1), 239.
 [http://dx.doi.org/10.1186/s12935-021-01946-4] [PMID:  33906641]

[93]
Weng, M.S.; Chang, J.H.; Hung, W.Y.; Yang, Y.C.; Chien, M.H. The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance. J. Exp. Clin. Cancer Res.,  2018, 37(1), 61.
 [http://dx.doi.org/10.1186/s13046-018-0728-0] [PMID:  29548337]
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DOI https://dx.doi.org/10.2174/1573406419666230103142021	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638
Medicinal Chemistry

Comparative Computational Screening of Natural-based Partial Agonists for PPARγ Receptor

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