Abstract
Objective: Hepatocellular carcinoma (HCC) is a widely occurring cancer ranking second in humans, with an incidence rate of approximately 1.6% per year in India. Experimental analysis of the Boeravinones or the Rotenoids classification of compounds present in the roots of the Boerhaavia diffusa Linn plant has shown a wide range of anti-cancer activity against liver hepatoblastoma.
Methods: Boeravinone B (BB) was screened from widely available Boeravinone A-E compounds based on a maximum drug-likeness score using Lipinski’s rule Five. BB was checked for anti-HCC activity by binding with the five receptors of VEGF, EGF, BCl2, Caspase-3 and Caspase-9 when compared with Sorafenib through molecular docking. GROMACS was used for simulating molecular dynamics.
Results: BB has shown a negative maximum internal energy score of -8.04, -8.42, -6.66, -8.33 and -7.74 Kcal/mol when compared to Sorafenib’s internal energy score of -6.55, -7.12, -4.05, -5.48 and -6.12 Kcal/mol for VEGFR, EGFR, BCl2, Caspase-3 and Caspase-9 respectively. Simulation using GROMACS has revealed that RMSD results BB forms a more stable complex with the Caspase-3 and EGFR after 19s and 15s of simulation time. RMSF analysis has characterized local changes on 170-190 residues and 860- 900 residues in C-alpha atoms of BB-Caspase-3 and BB-EGFR complexes revealed protein flexibility.
Conclusion: MMPBSA score of BB docked Caspase-3 and EGFR complexes were found to be -62.178 and -42.84 KJ/mol.
Keywords: Boeravinone B, Boerhaavia diffusa Linn, hepatocellular carcinoma, sorafenib, EGFR, Caspase-3.
Graphical Abstract
[1]
Rawla, P.; Sunkara, T.; Muralidharan, P.; Raj, J.P. Update in global trends and aetiology of hepatocellular carcinoma. Contemp. Oncol. (Pozn.), 2018, 22(3), 141-150.
[http://dx.doi.org/10.5114/wo.2018.78941] [PMID: 30455585]
[http://dx.doi.org/10.5114/wo.2018.78941] [PMID: 30455585]
[2]
Jindal, A.; Thadi, A.; Shailubhai, K. Hepatocellular carcinoma: Etiology and current and future drugs. J. Clin. Exp. Hepatol., 2019, 9(2), 221-232.
[http://dx.doi.org/10.1016/j.jceh.2019.01.004] [PMID: 31024205]
[http://dx.doi.org/10.1016/j.jceh.2019.01.004] [PMID: 31024205]
[3]
Suganya, V.; Anuradha, V. In silico molecular docking of astaxanthin and sorafenib with different apoptotic proteins involved in hepatocellular carcinoma. Biocatal. Agric. Biotechnol., 2019, 19, 101076.
[http://dx.doi.org/10.1016/j.bcab.2019.101076]
[http://dx.doi.org/10.1016/j.bcab.2019.101076]
[4]
Chaudhary, G.; Dantu, P.K. Morphological, phytochemical and pharmacological, studies on Boerhaavia diffusa L. J. Med. Plants Res., 2011, 5, 2125-2130.
[5]
Huang, Y.; Sun, Y.; Wang, W.W.; Zhang, L. Boeravinone B a natural rotenoid exerts anticancer activity via inducing internalization and degradation of inactivated EGFR and ErbB2 in human colon cancer cells. Am. J. Transl. Res., 2018, 10(12), 4183-4192.
[PMID: 30662661]
[PMID: 30662661]
[6]
Bairwa, K.; Jachak, S.M. Anti-inflammatory potential of a lipid-based formulation of a rotenoid-rich fraction prepared from Boerhavia diffusa. Pharm. Biol., 2015, 53(8), 1231-1238.
[http://dx.doi.org/10.3109/13880209.2014.971382] [PMID: 25864706]
[http://dx.doi.org/10.3109/13880209.2014.971382] [PMID: 25864706]
[7]
Joo, Y.Y.; Jang, J.W.; Lee, S.W.; Yoo, S.H.; Kwon, J.H.; Nam, S.W.; Bae, S.H.; Choi, J.Y.; Yoon, S.K. Circulating pro- and anti-angiogenic factors in multi-stage liver disease and hepatocellular carcinoma progression. Sci. Rep., 2019, 9(1), 9137.
[http://dx.doi.org/10.1038/s41598-019-45537-w] [PMID: 31235729]
[http://dx.doi.org/10.1038/s41598-019-45537-w] [PMID: 31235729]
[8]
Hu, B.; Sun, D.; Sun, C.; Sun, Y.F.; Sun, H.X.; Zhu, Q.F.; Yang, X.R.; Gao, Y.B.; Tang, W.G.; Fan, J.; Maitra, A.; Anders, R.A.; Xu, Y. A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma. Biochem. Biophys. Res. Commun., 2015, 468(4), 525-532.
[http://dx.doi.org/10.1016/j.bbrc.2015.10.031] [PMID: 26482853]
[http://dx.doi.org/10.1016/j.bbrc.2015.10.031] [PMID: 26482853]
[9]
Praveen Kumar, P.K.; Sivanandham, M.; Damodharan, L. In silico binding analysis of Withanolides with the Human GM-CSFR. Pak. J. Pharm. Sci., 2016, 29(4), 1279-1286.
[PMID: 27393453]
[PMID: 27393453]
[10]
Bhoi, S.R.; Panda, N.R.; Rawal, R.M.; Raval, M.K. In silico analysis of hexokinase-I and II as potential drug targets in cancer. Pharm. Biol. Eval., 2016, 3, 351-359.
[11]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[12]
Laskowski, R.A.; Swindells, M.B. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Model., 2011, 51(10), 2778-2786.
[http://dx.doi.org/10.1021/ci200227u] [PMID: 21919503]
[http://dx.doi.org/10.1021/ci200227u] [PMID: 21919503]
[13]
Gangadharappa, B.S.; Sharath, R.; Revanasiddappa, P.D.; Chandramohan, V.; Balasubramaniam, M.; Vardhineni, T.P. Structural insights of metallo-beta-lactamase revealed an effective way of inhibition of enzyme by natural inhibitors. J. Biomol. Struct. Dyn., 2020, 38(13), 3757-3771.
[http://dx.doi.org/10.1080/07391102.2019.1667265] [PMID: 31514687]
[http://dx.doi.org/10.1080/07391102.2019.1667265] [PMID: 31514687]
[14]
Praveen, P.K.P.; Subasree, S.; Arthi, U.; Mobashir, M.; Gowda, C.; Revanasidappa, P.D. T-cell epitope-based vaccine design against nipah virus by reverse vaccinology approach. Comb. Chem High. Screen., 2020, 23, 788-796.
[15]
Agrawal, B.; Das, S.; Pandey, A. Boerhaavia diffusa Linn: A review on its phytochemical and pharmacological profile. Asian. J. Appl Sci., 2011, 4(7), 7.
[http://dx.doi.org/10.3923/ajaps.2011.663.684]
[http://dx.doi.org/10.3923/ajaps.2011.663.684]
[16]
Genheden, S.; Ryde, U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov., 2015, 10(5), 449-461.
[http://dx.doi.org/10.1517/17460441.2015.1032936] [PMID: 25835573]
[http://dx.doi.org/10.1517/17460441.2015.1032936] [PMID: 25835573]
[17]
Wang, C.; Greene, D.; Xiao, L.; Qi, R.; Luo, R. Recent developments and applications of the MMPBSA method. Front. Mol. Biosci., 2018, 4, 87.
[http://dx.doi.org/10.3389/fmolb.2017.00087] [PMID: 29367919]
[http://dx.doi.org/10.3389/fmolb.2017.00087] [PMID: 29367919]
[18]
Zhu, S.; Hoshida, Y. Molecular heterogeneity in hepatocellular carcinoma. Hepat. Oncol., 2018, 5(1), HEP10.
[http://dx.doi.org/10.2217/hep-2018-0005] [PMID: 30302198]
[http://dx.doi.org/10.2217/hep-2018-0005] [PMID: 30302198]
[19]
Yoshida, M.; Yamashita, T.; Okada, H.; Oishi, N.; Nio, K.; Hayashi, T.; Nomura, Y.; Hayashi, T.; Asahina, Y.; Ohwada, M.; Sunagozaka, H.; Takatori, H.; Colombo, F.; Porretti, L.; Honda, M.; Kaneko, S. Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90. Sci. Rep., 2017, 7(1), 11292.
[http://dx.doi.org/10.1038/s41598-017-11848-z] [PMID: 28900199]
[http://dx.doi.org/10.1038/s41598-017-11848-z] [PMID: 28900199]
[20]
Elgemeie, G.H.; Fathy, N.M.; Farag, A.B.; Alkhursani, S.A. Design, synthesis, molecular docking and anti-hepatocellular carcinoma evaluation of novel acyclic pyridine thioglycosides. Nucleosides Nucleotides Nucleic Acids, 2018, 37(3), 186-198.
[http://dx.doi.org/10.1080/15257770.2018.1450508] [PMID: 29608403]
[http://dx.doi.org/10.1080/15257770.2018.1450508] [PMID: 29608403]
[21]
Krishnamoorthy, P.K.P.; Kamal, M.A.; Warsi, M.K.; Alnajeebi, A.M.; Ali, H.A.; Helmi, N.; Izhari, M.A.; Mustafa, S.; Firoz, A.; Mobashir, M. In-silico study reveals immunological signalling pathways, their genes and potential herbal drug targets in ovarian cancer. Inform. Medicine Unlocked, 2020, 20(100422), 1-8.
[22]
Karthick, J.; Praveen Kumar, P.K. A computational analysis to study the application of lipid nanotechnology in the field of drug delivery to treat liver diseases. Research J. Engineering and Tech., 2013, 4, 284-287.
[23]
Wang, J.; Sun, P.; Chen, Y.; Yao, H.; Wang, S. Novel 2-phenyloxypyrimidine derivative induces apoptosis and autophagy via inhibiting PI3K pathway and activating MAPK/ERK signaling in hepatocellular carcinoma cells. Sci. Rep., 2018, 8(1), 10923.
[http://dx.doi.org/10.1038/s41598-018-29199-8] [PMID: 30026540]
[http://dx.doi.org/10.1038/s41598-018-29199-8] [PMID: 30026540]
[24]
El-Miligy, M.M.M.; Rida, S.M.; Ashour, F.A.; Badr, M.H.; El-Bassiony, E.M.; EI-Demellawy, M.A.; Omar, A.M. Dual inhibitors of hepatitis C virus and hepatocellular carcinoma: Design, synthesis and docking studies; Futur; Sci OA, 2018, p. 4.
[25]
Verma, S.; Singh, A.; Mishra, A. Taxifolin acts as type I inhibitor for VEGFR-2 kinase: Stability evaluation by molecular dynamic simulation. J. Appl. Pharm. Sci., 2012, 2, 41-46.
[26]
Miettinen, M.; Rikala, M.S.; Rys, J.; Lasota, J.; Wang, Z.F. Vascular endothelial growth factor receptor 2 as a marker for malignant vascular tumors and mesothelioma: An immunohistochemical study of 262 vascular endothelial and 1640 nonvascular tumors. Am. J. Surg. Pathol., 2012, 36(4), 629-639.
[http://dx.doi.org/10.1097/PAS.0b013e318243555b] [PMID: 22314185]
[http://dx.doi.org/10.1097/PAS.0b013e318243555b] [PMID: 22314185]
[27]
Boraei, A.T.A.; Ashour, H.K.; El Tamany, E.S.H.; Abdelmoaty, N.; El-Falouji, A.I.; Gomaa, M.S. Design and synthesis of new phthalazine-based derivatives as potential EGFR inhibitors for the treatment of hepatocellular carcinoma. Bioorg. Chem., 2019, 85, 293-307.
[http://dx.doi.org/10.1016/j.bioorg.2018.12.039] [PMID: 30654221]
[http://dx.doi.org/10.1016/j.bioorg.2018.12.039] [PMID: 30654221]
[28]
Shang, N.; Bank, T.; Ding, X.; Breslin, P.; Li, J.; Shi, B.; Qiu, W. Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation. Cell Death Dis., 2018, 9(5), 558.
[http://dx.doi.org/10.1038/s41419-018-0617-7] [PMID: 29752472]
[http://dx.doi.org/10.1038/s41419-018-0617-7] [PMID: 29752472]
[29]
Karthick, J.; Praveen, K.P.K.; Krishna Moorthy, P. Analysis of targeted delivery of ribavirin to hepatic cells in treatment of Hepato-cellular carcinoma. World J. Pharm. Pharm. Sci., 2013, 2, 5681-5696.
[30]
Ahmed, W.; Mofed, D.; Zekri, A.R.; El-Sayed, N.; Rahouma, M.; Sabet, S. Antioxidant activity and apoptotic induction as mechanisms of action of Withania somnifera (Ashwagandha) against a hepatocellular carcinoma cell line. J. Int. Med. Res., 2018, 46(4), 1358-1369.
[http://dx.doi.org/10.1177/0300060517752022] [PMID: 29392963]
[http://dx.doi.org/10.1177/0300060517752022] [PMID: 29392963]
[31]
Kirubhanand, C.; Selvaraj, J.; Rekha, U.V.; Vishnupriya, V.; Nalini, D.; Mohan, S.K.; Vijayalakshmi, P.; Rajalakshmi, M.; Ponnulakshmi, R. Molecular docking data of piperine with Bax, Caspase 3, Cox 2 and Caspase 9. Bioinformation, 2020, 16(6), 458-461.
[http://dx.doi.org/10.6026/97320630016458] [PMID: 32884209]
[http://dx.doi.org/10.6026/97320630016458] [PMID: 32884209]
[32]
Labib, M.B.; Philoppes, J.N.; Lamie, P.F.; Ahmed, E.R. Azole-hydrazone derivatives: Design, synthesis, in vitro biological evaluation, dual EGFR/HER2 inhibitory activity, cell cycle analysis and molecular docking study as anticancer agents. Bioorg. Chem., 2018, 76, 67-80.
[http://dx.doi.org/10.1016/j.bioorg.2017.10.016] [PMID: 29153588]
[http://dx.doi.org/10.1016/j.bioorg.2017.10.016] [PMID: 29153588]
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