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Letters in Drug Design & Discovery

Editor-in-Chief

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

Research Article

Computational Investigation of Zerumbone as an Inhibitor of TNF-alpha Using Molecular Dynamics and Molecular Docking Methods

Author(s): Salam Pradeep Singh, Khumukcham Nongalleima, Ningthoujam Indrajit Singh, Wahengbam Kabita Chanu, Thiyam Ramsing Singh and Chingakham Brajakisor Singh*

Volume 18, Issue 3, 2021

Published on: 10 November, 2020

Page: [258 - 268] Pages: 11

DOI: 10.2174/1570180817999201110112221

Price: $65

Abstract

Background: There are several reports on the anti-cancer property of zerumbone, such as in breast, cervical and ovarian cancer. But the investigation of the actual protein target has been the least concerned and there are few reports on the inhibitory effect of zerumbone against specific cancer-causing proteins and enzymes. Therefore, further investigation is required at a much deeper molecular level.

Objective: This study aimed to determine the anti-proliferative activity of Zerumbone against cervical cancer cell and assess its TNF-α enzyme inhibitory action.

Methods: The investigation emphasized the anti-cancer activity of zerumbone against HeLa cells and its subsequent TNF-α assay. Furthermore, computational studies on Zerumbone as an inhibitor of TNF-α were carried out using computational techniques such as docking and MD simulations.

Results and Discussion: From the molecular docking analysis, it was observed and substantiated that the α,β-Unsaturated carbonyl scaffold is the main driving force for anti-cancer activity of zerumbone and inhibition of TNF-α.

Conclusion: Zerumbone might be a potent anti-cancer agent targeting the HeLa cancer cell lines and inhibiting the TNF-α enzyme.

Keywords: Zerumbone, TNF-α, docking, MD simulation, cervical cancer, HeLa, ADME-toxicity.

Graphical Abstract
[1]
Kumar, V.; Abbas, A.K.; Fausto, N.; Mitchell, R.N. Robbins Basic Pathology, 8th ed; Saunders Elsevier, 2007, pp. 718-721.
[2]
Liu, L.; Yang, X.; Chen, X.; Kan, T.; Shen, Y.; Chen, Z.; Hu, Z. Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis. Mol. Biol. Rep., 2012, 39(3), 2683-2688.
[http://dx.doi.org/10.1007/s11033-011-1022-9] [PMID: 21670964]
[3]
Duarte, I.; Santos, A.; Sousa, H.; Catarino, R.; Pinto, D.; Matos, A.; Pereira, D.; Moutinho, J.; Canedo, P.; Machado, J.C.; Medeiros, R. G-308A TNF-alpha polymorphism is associated with an increased risk of invasive cervical cancer. Biochem. Biophys. Res. Commun., 2005, 334(2), 588-592.
[http://dx.doi.org/10.1016/j.bbrc.2005.06.137] [PMID: 16009345]
[4]
Korneev, K.V.; Atretkhany, K.N.; Drutskaya, M.S.; Grivennikov, S.I.; Kuprash, D.V.; Nedospasov, S.A. TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis. Cytokine, 2017, 89, 127-135.
[http://dx.doi.org/10.1016/j.cyto.2016.01.021] [PMID: 26854213]
[5]
Bachmeier, B.E.; Mirisola, V.; Romeo, F.; Generoso, L.; Esposito, A.; Dell’eva, R.; Blengio, F.; Killian, P.H.; Albini, A.; Pfeffer, U. Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin. Cell. Physiol. Biochem., 2010, 26(3), 471-482.
[http://dx.doi.org/10.1159/000320570] [PMID: 20798532]
[6]
Amoroso, M.R.; Matassa, D.S.; Agliarulo, I.; Avolio, R.; Maddalena, F.; Condelli, V.; Landriscina, M.; Esposito, F. Chapter Seven- Stress-Adaptive response in ovarian cancer drug resistance: Role of TRAP1 in oxidative metabolism-driven inflammation. Adv. Protein Chem. Struct. Biol., 2017, 108, 163-198.
[http://dx.doi.org/10.1016/bs.apcsb.2017.01.004] [PMID: 28427560]
[7]
Fatima, A.; Abdul, A.B.; Abdullah, R.; Karjiban, R.A.; Lee, V.S. Binding mode analysis of zerumbone to key signal proteins in the tumor necrosis factor pathway. Int. J. Mol. Sci., 2015, 16(2), 2747-2766.
[http://dx.doi.org/10.3390/ijms16022747] [PMID: 25629232]
[8]
Melagraki, G.; Ntougkos, E.; Rinotas, V.; Papaneophytou, C.; Leonis, G.; Mavromoustakos, T.; Kontopidis, G.; Douni, E.; Afantitis, A.; Kollias, G. Cheminformatics-aided discovery of smallmoleculeProtein-Protein Interaction (PPI) dual inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL). PLoS Comput. Biol., 2017, 13(4), e1005372.
[http://dx.doi.org/10.1371/journal.pcbi.1005372] [PMID: 28426652]
[9]
von Maltzan, K.; Tan, W.; Pruett, S.B. Investigation of the role of TNF-α converting enzyme (TACE) in the inhibition of cell surface and soluble TNF-α production by acute ethanol exposure. PLoS One, 2012, 7(2), e29890.
[http://dx.doi.org/10.1371/journal.pone.0029890] [PMID: 22319556]
[10]
Yob, N.J.; Jofrry, S.M.; Affandi, M.M.; Teh, L.K.; Salleh, M.Z.; Zakaria, Z.A. Zingiber zerumbet (L.) Smith: A review of its ethnomedicinal, chemical, and pharmacological uses. Evid. Based Complement. Alternat. Med., 2011, 2011, 543216.
[http://dx.doi.org/10.1155/2011/543216] [PMID: 21584247]
[11]
Murakami, A.; Takahashi, D.; Kinoshita, T.; Koshimizu, K.; Kim, H.W.; Yoshihiro, A.; Nakamura, Y.; Jiwajinda, S.; Terao, J.; Ohigashi, H. Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: The alpha,beta-unsaturated carbonyl group is a prerequisite. Carcinogenesis, 2002, 23(5), 795-802.
[http://dx.doi.org/10.1093/carcin/23.5.795] [PMID: 12016152]
[12]
Abdelwahab, S.I.; Abdul, A.B.; Devi, N.; Taha, M.M.; Al-zubairi, A.S.; Mohan, S.; Mariod, A.A. Regression of cervical intraepithelial neoplasia by zerumbone in female Balb/c mice prenatally exposed to diethylstilboestrol: Involvement of mitochondria-regulated apoptosis. Exp. Toxicol. Pathol., 2010, 62(5), 461-469.
[http://dx.doi.org/10.1016/j.etp.2009.06.005] [PMID: 19581075]
[13]
Abdul, A.B.; Abdelwahab, S.I.; Bin Jalinas, J.; Al-Zubairi, A.S.; Taha, M.M. Combination of zerumbone and cisplatin to treat cervical intraepithelial neoplasia in female BALB/c mice. Int. J. Gynecol. Cancer, 2009, 19(6), 1004-1010.
[http://dx.doi.org/10.1111/IGC.0b013e3181a83b51] [PMID: 19820360]
[14]
Abdelwahab, S.I.; Abdul, A.B.; Zain, Z.N.; Hadi, A.H. Zerumbone inhibits interleukin-6 and induces apoptosis and cell cycle arrest in ovarian and cervical cancer cells. Int. Immunopharmacol., 2012, 12(4), 594-602.
[http://dx.doi.org/10.1016/j.intimp.2012.01.014] [PMID: 22330084]
[15]
Takada, Y.; Murakami, A.; Aggarwal, B.B. Zerumbone abolishes NF-kappaB and IkappaBalpha kinase activation leading to suppression of antiapoptotic and metastatic gene expression, upregulation of apoptosis, and downregulation of invasion. Oncogene, 2005, 24(46), 6957-6969.
[http://dx.doi.org/10.1038/sj.onc.1208845] [PMID: 16007145]
[16]
Du, X.; Li, Y.; Xia, Y.L.; Ai, S.M.; Liang, J.; Sang, P.; Ji, X.L.; Liu, S.Q. Insights into Protein-Ligand Interactions: Mechanisms, Models, and Methods. Int. J. Mol. Sci., 2016, 17(2), 144-164.
[http://dx.doi.org/10.3390/ijms17020144] [PMID: 26821017]
[17]
Scott, W.R.P.; Huenenberger, P.H.; Tironi, I.G.; Mark, A.E.; Billeter, S.R.; Gunsteren, W.F.V. The GROMOS Biomolecular Simulation Package. J. Phys. Chem. A, 1999, 103, 3596-3607.
[http://dx.doi.org/10.1021/jp984217f]
[18]
Schüttelkopf, A.W.; van Aalten, D.M. PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr., 2004, 60(Pt 8), 1355-1363.
[http://dx.doi.org/10.1107/S0907444904011679] [PMID: 15272157]
[19]
Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A Gen. Phys., 1988, 38(6), 3098-3100.
[http://dx.doi.org/10.1103/PhysRevA.38.3098] [PMID: 9900728]
[20]
Amslinger, S. The tunable functionality of alpha,beta-unsaturated carbonyl compounds enables their differential application in biological systems. Chem. Med. Chem., 2010, 5(3), 351-356.
[http://dx.doi.org/10.1002/cmdc.200900499] [PMID: 20112330]
[21]
Rivas, M.A.; Carnevale, R.P.; Proietti, C.J.; Rosemblit, C.; Beguelin, W.; Salatino, M.; Charreau, E.H.; Frahm, I.; Sapia, S.; Brouckaert, P.; Elizalde, P.V.; Schillaci, R. TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways. Exp. Cell Res., 2008, 314(3), 509-529.
[http://dx.doi.org/10.1016/j.yexcr.2007.10.005] [PMID: 18061162]
[22]
He, M.M.; Smith, A.S.; Oslob, J.D.; Flanagan, W.M.; Braisted, A.C.; Whitty, A.; Cancilla, M.T.; Wang, J.; Lugovskoy, A.A.; Yoburn, J.C.; Fung, A.D.; Farrington, G.; Eldredge, J.K.; Day, E.S.; Cruz, L.A.; Cachero, T.G.; Miller, S.K.; Friedman, J.E.; Choong, I.C.; Cunningham, B.C. Small-molecule inhibition of TNF-alpha. Science, 2005, 310(5750), 1022-1025.
[http://dx.doi.org/10.1126/science.1116304] [PMID: 16284179]
[23]
Rahman, H.S.; Rasedee, A.; Yeap, S.K.; Othman, H.H.; Chartrand, M.S.; Namvar, F.; Abdul, A.B.; How, C.W. Biomedical properties of a natural dietary plant metabolite, zerumbone, in cancer therapy and chemoprevention trials. BioMed Res. Int., 2014, 2014, 920742.
[http://dx.doi.org/10.1155/2014/920742] [PMID: 25025076]
[24]
Singh, S.P.; Singh, N.I.; Nongalleima, K. Molecular docking, MD simulation, DFT and ADME-toxicity study on analogs of zerumbone against IKK-β enzyme as anti-cancer agents. Netw. Model. Anal. Health Inform. Bioinform., 2018, 7, 7.
[http://dx.doi.org/10.1007/s13721-018-0171-3]
[25]
Singh, S.P.; Nongalleima, K.; Singh, N.I.; Doley, P.; Singh, C.B.; Singh, T.R.; Sahoo, D. Zerumbone reduces proliferation of HCT116 colon cancer cells by inhibition of TNF-alpha. Sci. Rep., 2018, 8(1), 4090.
[http://dx.doi.org/10.1038/s41598-018-22362-1] [PMID: 29511228]
[26]
Kalantari, K.; Moniri, M.; Boroumand Moghaddam, A.; Abdul Rahim, R.; Bin Ariff, A.; Izadiyan, Z.; Mohamad, R. A review of the biomedical applications of Zerumbone and the techniques for its extraction from ginger rhizomes. Molecules, 2017, 22(10), 1645.
[http://dx.doi.org/10.3390/molecules22101645] [PMID: 28974019]
[27]
Ghosh, D.; Jana, J. Frontier orbital and density functional study of the variation of the hard-soft behavior of monoborane (BH3) and boron trifluoride (BF3) as a function of angles of reorganization from planar (D3h) to pyramidal (C3v) shape. Int. J. Quantum Chem., 2003, 92, 484-505.
[http://dx.doi.org/10.1002/qua.10482]

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