Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Evaluation of Kaempferol as AKT Dependent mTOR Regulator via Targeting FKBP-12 in Hepatocellular Carcinoma: An In silico Approach

Author(s): Pooja Siniprasad, Bhagyalakshmi Nair, Vaisali Balasubramaniam, Prashanth Sadanandan, Puliyapally Krishnan Namboori* and Lekshmi Reghu Nath*

Volume 17, Issue 11, 2020

Page: [1401 - 1408] Pages: 8

DOI: 10.2174/1570180817999200623115703

Price: $65

Abstract

Background: Hepatocellular carcinomas (HCCs) are inherently chemotherapy-resistant tumors with about 30-50% activation of PI3K/Akt/mTOR pathway, and this pathway is not aberrant in normal cells. Therefore, targeting the PI3K/Akt/mTOR pathway has become a promising strategy in drug designing to combat liver cancer. Recently, many studies with phytochemicals suggest few classes of compounds, especially flavonoids, to be useful in down-regulating the PI3K/Akt/mTOR pathway corresponding to HCC. In the present study, an attempt is made to explore flavonoids, from which the best mTORC1 inhibitor against hepatocellular carcinoma is selected using computational molecular modeling.

Methods: In the present study, we performed a virtual screening method with phytochemicals of flavonoid category. To ensure proper bioavailability and druggability, pharmacokinetic and interaction parameters have been used to screen the molecules. The target protein molecules have been selected from the RCSB. The interaction studies have been conducted using Biovia Discovery Studio client version 17.2.0.1.16347 and the pharmacokinetic predictions have been made through ADMET SAR. The responsiveness towards the regulation of the mTOR pathway varies from person to person, demanding a pharmacogenomic approach in the analysis. The genetic variants (Single Nucleotide Variants-SNVs) corresponding to the mutations have been identified.

Results and Discussions: The study identified phytoconstituents with better interaction with receptor FKBP12, a Rapamycin binding domain which is the target of Rapamycin and its analogues for mTORC1 inhibition in HCC. Another protein, ‘AKT serine/threonine-protein kinase’ has been identified, which is associated with activation of mTORC1. The molecular interaction studies (docking studies) and ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were used to identify the affinity between selected phytoconstituents as mTORC1 inhibitor against Hepatocellular carcinoma. The docking studies support Kaempferol to be a potential ligand with docking score values of 33.4 (3CQU-3D structure of AKT1)] and 27.3 (2FAP-3D structure of FRB domain of mTOR) respectively as compared to that of standard drug Everolimus with 24.4 (3CQU-3D structure of AKT1) and 20.1 (2FAP-3D structure of FRB domain of mTOR) respectively. Docking studies along with ADMET results show that Kaempferol has favorable drug likeliness properties and binds to the same active site (site1) of the targeted proteins (3CQU-3D structure of AKT1) and (2FAP-3D structure of FRB domain of mTOR) where the standard drug Everolimus is known to bind.

Conclusion: The study exhibited that Kaempferol had a better binding affinity towards the receptor FKBP12, a Rapamycin Binding Domain and AKT serine/threonine-protein kinase resulting in its better efficacy in the mTORC1 inhibition as when compared with standard drug Everolimus against HCC. To the best of our knowledge, no studies have been reported on Kaempferol as mTORC1 inhibitor against Hepatocellular carcinoma.

Keywords: mTORC1, phytoconstituents, hepatocellular carcinoma, molecular docking, rapamycin binding domain (FKBP12), AKT serine/threonine-protein kinase.

Graphical Abstract
[1]
Matter, M.S.; Decaens, T.; Andersen, J. B. Targetting mTOR Pathway In Hepatocellular Carcinoma: Current State And Future Trends. J. Hepatol., 2014, 60(4), 855-865.
[http://dx.doi.org/10.1016/j.jhep.2013.11.031 ] [PMID: 24308993]
[2]
Balogh, J.; Victor, D., III; Emad, H. Asham,Sherilyn Gordon Burroughs,Maha Boktour, Ashish Saharia, Xian Li, R Mark Ghobrial, and Howard P Monsour, Jr, Hepatocellular Carcinoma A rieview. J. Hepatocell. Carcinoma, 2016, 3, 41-53.
[http://dx.doi.org/10.2147/JHC.S61146 ] [PMID: 27785449]
[3]
Crissien, A.M.; Frenette, C. Current management of hepatocellular carcinoma. Gastroenterol. Hepatol. (N. Y.), 2014, 10(3), 153-161.
[PMID: 24829542]
[4]
Rinella, M.E. Nonalcoholic fatty liver disease: a systematic review. JAMA, 2015, 313(22), 2263-2273.
[http://dx.doi.org/10.1001/jama.2015.5370 ] [PMID: 26057287]
[5]
Waller, L.P.; Deshpande, V.; Pyrsopoulos, N. Hepatocellular carcinoma: A comprehensive review. World J. Hepatol., 2015, 7(26), 2648-2663.
[http://dx.doi.org/10.4254/wjh.v7.i26.2648 ] [PMID: 26609342]
[6]
Moeini, A.; Cornellà, H.; Villanueva, A. Emerging signaling pathways in hepatocellular carcinoma. Liver Cancer, 2012, 1(2), 83-93.
[http://dx.doi.org/10.1159/000342405 ] [PMID: 24159576]
[7]
Walker, S.; Wankell, M.; Ho, V.; White, R.; Deo, N.; Devine, C.; Dewdney, B.; Bhathal, P.; Govaere, O.; Roskams, T.; Qiao, L.; George, J.; Hebbard, L. Targeting mTOR and Src restricts hepatocellular carcinoma growth in a novel murine liver cancer model. PLoS One, 2019, 14(2), e0212860
[http://dx.doi.org/10.1371/journal.pone.0212860 ] [PMID: 30794695]
[8]
Ferrin, G; Guerrero, M Dela Mata, M Activation of mTOR Signaling pathway in Hepatocellular Carcinoma International journal of Molecular Science, 2020, 21(4), 1266
[9]
Saxton, R.A.; Sabatini, D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell, 2017, 168(6), 960-976.
[http://dx.doi.org/10.1016/j.cell.2017.02.004 ] [PMID: 28283069]
[10]
Okuno, T.; Kakehashi, A.; Ishii, N.; Fujioka, M.; Gi, M.; Wanibuchi, H.G. H; mTOR activation in liver tumors is associated with metabolic syndrome and non alcoholic steatohepatits in both mouse models and humans. Cancers (Basel), 2018, 10(12), 465.
[http://dx.doi.org/10.3390/cancers10120465 ] [PMID: 30469530]
[11]
Laplante, M.; Sabatini, D.M. mTOR signaling at a glance. J. Cell Sci., 2009, 122(Pt 20), 3589-3594.
[http://dx.doi.org/10.1242/jcs.051011 ] [PMID: 19812304]
[12]
Bond, P. Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance. J. Int. Soc. Sports Nutr., 2016, 13, 8.
[http://dx.doi.org/10.1186/s12970-016-0118-y ] [PMID: 26937223]
[13]
Vian, D.S.; Reis, F. Alves, R Therapeutic use of mTOR Inhibitor In Renal Disease: Advances Drawbacks And Challenges. Oxid. Med. Cell. Longev., 2018, 17.
[14]
Cheaib, B.; Auguste, A.; Leary, A. The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges. Chin. J. Cancer, 2015, 34(1), 4-16.
[http://dx.doi.org/10.5732/cjc.014.10289 ] [PMID: 25556614]
[15]
Xie, J. X,Wang, C.G. Proud, mTOR inhibitors in cancer therapy. F1000 Res., 2016, (5), 2078.
[http://dx.doi.org/10.12688/f1000research.9207.1]
[16]
Zubair, H.; Azim, S.; Ahmad, A.; Khan, M.A.; Patel, G.K.; Singh, S.; Singh, A.P. Cancer chemoprevention by phytochemicals: Nature’s healing touch. Molecules, 2017, 22(3), 395.
[http://dx.doi.org/10.3390/molecules22030395 ] [PMID: 28273819]
[17]
Dehghan Shahreza, F. Oxidative stress, free radicals, kidney disease and plant antioxidants. Immunopathol Persa., 2017, 3(2), e11
[http://dx.doi.org/10.15171/ipp.2017.03]
[18]
Estefanny Ruiz Garcia. Eliana Alviarez Gutierrez; Fabiana Cristina Silveira Alves de Melo; Romulo Dias Novaes; and Reggiani Vilela Gonçalves: Flavonoids effect on Hepatocellular carcinoma in murine models: A systematic review; Evidence Bassed Complementary and Alternative Medicine, 2018, p. 23.
[19]
Rampogu, S.; Parate, S.; Parameswaran, S.; Park, C.; Baek, A.; Son, M.; Park, Y.; Park, S.J.; Lee, K.W. Natural compounds as potential Hsp90 inhibitors for breast cancer-Pharmacophore guided molecular modelling studies. Comput. Biol. Chem., 2019., 83107113
[http://dx.doi.org/10.1016/j.compbiolchem.2019.107113 ] [PMID: 31493740]
[20]
Kurangi, B.K.; Jalalpure, S.S. Review of selected herbal phytoconstituent for potential melanoma treatment. Indian J Health Sci Biomed Res, 2018, 11, 3-11.
[http://dx.doi.org/10.4103/kleuhsj.kleuhsj_319_17]
[21]
Srimai, V.; Ramesh, M.; Satya, P.K.; Parthasarathy, T. Computer-aided design of selective Cytochrome P450 inhibitors and docking studies of alkyl resorcinol derivatives. Med. Chem. Res., 2013, 22(11), 5314-5323.
[http://dx.doi.org/10.1007/s00044-013-0532-5]
[22]
Dalia, M. Kopustinskiene; Valdas,Jakstas; Arunas,Savickas; Jurga,Bernatoniene, Flavanoids as Anticancer Agents. Nutrient, 2020, 12(2), 457.
[23]
Rodriguez-Garcia, C Sanchez-Quesada Dietary Flavanoids as Cancer Chemopreventive Agent: An Updated review of Human Studies, Antioxidant, 2019, (8), 137
[24]
Yang, H; Lou, C; Sun, L Li, Jie; Cai, Y; Wang, Z; Li, W; Liu, G; Tang, Y. admetSAR 2.0:web-service for prediction and optimization of chemical ADMET properties. Bioinformatics, 2019, 15;35(6), 1067-1069.
[25]
Shomit, S.P,R; Timothy, S,m David, Regulation of mTORC1 complex 1 pathway by nutrients, growth factor and stress. Mol. Cell, 2010, 40(2), 310-322.
[http://dx.doi.org/10.1016/j.molcel.2010.09.026 ] [PMID: 20965424]
[26]
Che, J.; Liang, B.; Zhang, Y.; Wang, Y.; Tang, J.; Shi, G. Kaempferol alleviates ox-LDL-induced apoptosis by up-regulation of autophagy via inhibiting PI3K/Akt/mTOR pathway in human endothelial cells. Cardiovasc. Pathol., 2017, 31(31), 57-62.
[http://dx.doi.org/10.1016/j.carpath.2017.08.001 ] [PMID: 28985493]
[27]
Thiyagarajan, V.; Lee, K.W.; Leong, M.K.; Weng, C.F. Potential natural mTOR inhibitors screened by in silico approach and suppress hepatic stellate cells activation. J. Biomol. Struct. Dyn., 2018, 36(16), 4220-4234.
[http://dx.doi.org/10.1080/07391102.2017.1411295 ] [PMID: 29183268]
[28]
Sukumaran, J.P.K.K.N. Pharmacogenomic analysis of individual variation in prostate cancer. International Journal of Research in Pharmaceutical Sciences., 2013, 4(1), 70-72.
[29]
Liu, Y.; Feng, X.Y.; Jia, W. Q; Jing,Z; Xu,R,W; Cheng,X,C; Identification of novel PI3Kδ inhibitor by docking, ADMET prediction and molecular dynamics simulations. Comput. Biol. Chem., 2019, (78), 190-204.
[http://dx.doi.org/10.1016/j.compbiolchem.2018.12.002 ] [PMID: 30557817]
[30]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007 ] [PMID: 24981612]
[31]
Bosco, D.; Balakrishnan, A.; Mishra, R.; Aneesh, T.P. Design, synthesis and pharmacological evaluation of 2-phenyl quinazolin-4-0ne derivatives as anticolorectal cancer and anti-inflammatory agents. Asian J. Chem., 2018, (30), 2677-2685.
[http://dx.doi.org/10.14233/ajchem.2018.21547]
[32]
Berman, H.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, I.; Shindyalov, I.; Bourne, P.E. “The Proten Data Bank”. Nucleic Acids Res, 28, 235-242. Berman, H., Henrick, K., Nakamura, H. and Markley, J.L. (2007) The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data. Nucleic Acids Res., 2000, 35, D301-D303.
[http://dx.doi.org/10.1093/nar/gkl971 ] [PMID: 17142228]
[33]
Han, B; Yu, YQ; Yang, QL; Shen, CY Wang, XJ Kaempferol induced autophagic cell death of hepatocellular carcinoma cell via activating AMPK signaling, oncotarget, 2017, (8), 86227-86239.
[34]
Bienert, S.; Waterhouse, A.; de Beer, T.A.P.; Tauriello, G.; Studer, G.; Bordoli, L.; Schwede, T. The SWISS-MODEL Repository-new features and functionality. Nucleic Acids Res., 2017, 45(D1), D313-D319.
[http://dx.doi.org/10.1093/nar/gkw1132 ] [PMID: 27899672]
[35]
Nair, B.; Anto, R.J.; Sabitha, M.; Nath, L.R. Kaempferol-mediated sensitization enhances chemotherapeutic efficacy of Sorafenib against Hepatocellular carcinoma: an in silico and in vitro approach. Adv. Pharm. Bull., 2020, 10(3), 472-476.
[36]
Sirous, H.; Chemi, G.; Campiani, G.; Brogi, S. An integrated in silico screening strategy for identifying promising disruptors of p53-MDM2 interaction. Comput. Biol. Chem., 2019, 83(83), 107105
[http://dx.doi.org/10.1016/j.compbiolchem.2019.107105 ] [PMID: 31473433]
[37]
Zhu, G; X Liu; Y, Yan; X, Hing kaempferol inhibit proliferation, migration and invasion of liver cancer HepG2 cell by down regulation of micro RNA-21,Int J immunopathol Pharmacol, 2018, (32)
[38]
Ren, J.; Lu, Y.; Qian, Y.; Chen, B.; Wu, T.; Ji, G. Recent progress regarding kaempferol for the treatment of various diseases. Exp. Ther. Med., 2019, 18(4), 2759-2776.
[http://dx.doi.org/10.3892/etm.2019.7886 ] [PMID: 31572524]
[39]
Vaisali, B; Krishnan Namboori, P K Tumor Hypoxia Mutation Detection Using Deep Learning- A Deep Drug Designing Strategy, International journal of scientific & technology research, 2019, 8133-137.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy