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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Methylaervine as Potential Lead Compound Against Cervical Carcinoma: Pharmacologic Mechanism Prediction based on Network Pharmacology

Author(s): Wenjia Dan, Yujie Xu, Hongling Gu, Jixiang Gao and Jiangkun Dai*

Volume 18, Issue 1, 2022

Published on: 28 July, 2021

Page: [73 - 80] Pages: 8

DOI: 10.2174/1573409917666210602162016

Abstract

Background: The discovery of therapeutic anticancer agents based on natural products is one of the current research focuses. Network pharmacology will broaden our understanding of drug actions by bioinformatics analysis.

Objective: To explore the potential and provide scientific evidence for methylaervine as a lead compound against cervical carcinoma.

Methods: Methylaervine was synthesized, and its activity against four cancer cell lines was evaluated by MTT assay. Pharmacokinetic properties were obtained by in silico approaches, and the pharmacologic mechanism was predicted by network pharmacology. Then we validated and investigated our predictions of candidate targets using a molecular docking study.

Results: Methylaervine was synthesized with a total yield of 54.9%, which displayed activity against HeLa (IC50 = 14.8 μM) with good predicted pharmacokinetic properties, thus it was considered a potential lead compound. The network pharmacology study indicated that methylaervine could act against cervical carcinoma by regulating the function of multiple pivotal targets, such as CTNNB1, PTPRJ, RPA1, and TJP1, mainly covering cell growth, cell motility, and cell proliferation. Moreover, docking analysis showed that hydrogen bonds and hydrophobic interactions were the main forms of interactions.

Conclusion: This work would provide new insight into the design of anti-cervical carcinoma drugs based on methylaervine.

Keywords: Methylaervine, synthesis, antitumor activity, ADME study, network pharmacology, docking

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[1]
Su, X.; Ma, B.; Hu, J.; Yu, T.; Zhuang, W.; Yang, L.; Li, G.; Wang, Y. Dual-responsive doxorubicin-conjugated polymeric micelles with aggregation-induced emission active bioimaging and charge conversion for cancer therapy. Bioconjug. Chem., 2018, 29(12), 4050-4061.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00671] [PMID: 30404436]
[2]
Lin, B.; Lu, X.; Li, N.; Xu, N.; Lin, J.M. Effect of Dai-Bai-Jie on the proliferation and migration of the A549 cells. Chin. Chem. Lett., 2020, 31(2), 476-478.
[http://dx.doi.org/10.1016/j.cclet.2019.07.066]
[3]
Karan, D.; Dubey, S.; Pirisi, L.; Nagel, A.; Pina, I.; Choo, Y.M.; Hamann, M.T. The marine natural product manzamine A inhibits cervical cancer by targeting the SIX1 protein. J. Nat. Prod., 2020, 83(2), 286-295.
[http://dx.doi.org/10.1021/acs.jnatprod.9b00577] [PMID: 32022559]
[4]
Dai, J.; Dan, W.; Schneider, U.; Wang, J. β-Carboline alkaloid monomers and dimers: Occurrence, structural diversity, and biological activities. Eur. J. Med. Chem., 2018, 157, 622-656.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.027] [PMID: 30125723]
[5]
Siveen, K.S.; Kuttan, G. Modulation of humoral immune responses and inhibition of proinflammatory cytokines and nitric oxide production by 10-methoxycanthin-6-one. Immunopharmacol. Immunotoxicol., 2012, 34(1), 116-125.
[http://dx.doi.org/10.3109/08923973.2011.586703] [PMID: 22176677]
[6]
Dejos, C.; Voisin, P.; Bernard, M.; Régnacq, M.; Bergès, T. Canthin-6-one displays antiproliferative activity and causes accumulation of cancer cells in the G2/M phase. J. Nat. Prod., 2014, 77(11), 2481-2487.
[http://dx.doi.org/10.1021/np500516v] [PMID: 25379743]
[7]
Kuo, P.C.; Shi, L.S.; Damu, A.G.; Su, C.R.; Huang, C.H.; Ke, C.H.; Wu, J.B.; Lin, A.J.; Bastow, K.F.; Lee, K.H.; Wu, T.S. Cytotoxic and antimalarial β-carboline alkaloids from the roots of Eurycoma longifolia. J. Nat. Prod., 2003, 66(10), 1324-1327.
[http://dx.doi.org/10.1021/np030277n] [PMID: 14575431]
[8]
Zhao, F.; Dai, J.K.; Liu, D.; Wang, S.J.; Wang, J.R. Synthesis and evaluation of ester derivatives of 10-hydroxycanthin-6-one as potential antimicrobial agents. Molecules, 2016, 21(3), 390.
[http://dx.doi.org/10.3390/molecules21030390] [PMID: 27007362]
[9]
Chen, S.J.; Cui, M.C. Systematic understanding of the mechanism of salvianolic acid A via computational target fishing. Molecules, 2017, 22(4), 644.
[http://dx.doi.org/10.3390/molecules22040644] [PMID: 28420179]
[10]
Jiang, Y.; Zhong, M.; Long, F.; Yang, R.; Zhang, Y.; Liu, T. Network pharmacology-based prediction of active ingredients and mechanisms of Lamiophlomis rotata (Benth.) Kudo against rheumatoid arthritis. Front. Pharmacol., 2019, 10, 1435.
[http://dx.doi.org/10.3389/fphar.2019.01435] [PMID: 31849678]
[11]
Dai, J.; Dan, W.; Ren, S.; Shang, C.; Wang, J. Design, synthesis and biological evaluations of quaternization harman analogues as potential antibacterial agents. Eur. J. Med. Chem., 2018, 160, 23-36.
[http://dx.doi.org/10.1016/j.ejmech.2018.10.012] [PMID: 30317023]
[12]
Kibble, M.; Saarinen, N.; Tang, J.; Wennerberg, K.; Mäkelä, S.; Aittokallio, T. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Nat. Prod. Rep., 2015, 32(8), 1249-1266.
[http://dx.doi.org/10.1039/C5NP00005J] [PMID: 26030402]
[13]
Davis, A.P.; Grondin, C.J.; Johnson, R.J.; Sciaky, D.; McMorran, R.; Wiegers, J.; Wiegers, T.C.; Mattingly, C.J. The comparative toxicogenomics database: Update 2019. Nucleic Acids Res., 2019, 47(D1), D948-D954.
[http://dx.doi.org/10.1093/nar/gky868] [PMID: 30247620]
[14]
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]
[15]
Song, X.; Zhang, Y.; Dai, E.; Du, H.; Wang, L. Mechanism of action of celastrol against rheumatoid arthritis: A network pharmacology analysis. Int. Immunopharmacol., 2019, 74, 105725.
[http://dx.doi.org/10.1016/j.intimp.2019.105725] [PMID: 31276975]
[16]
Yu, G.; Wang, L.G.; Han, Y.; He, Q.Y. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5), 284-287.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[17]
Pham, T.A.; Jain, A.N. Parameter estimation for scoring protein-ligand interactions using negative training data. J. Med. Chem., 2006, 49(20), 5856-5868.
[http://dx.doi.org/10.1021/jm050040j] [PMID: 17004701]
[18]
Dai, J.; Dan, W.; Li, N.; Wang, R.; Zhang, Y.; Li, N.; Wang, R.; Wang, J. Synthesis and antibacterial activity of C2 or C5 modified and D ring rejiggered canthin-6-one analogues. Food Chem., 2018, 253, 211-220.
[http://dx.doi.org/10.1016/j.foodchem.2018.01.166] [PMID: 29502823]
[19]
Pai, S.G.; Carneiro, B.A.; Mota, J.M.; Costa, R.; Leite, C.A.; Barroso-Sousa, R.; Kaplan, J.B.; Chae, Y.K.; Giles, F.J. Wnt/beta-catenin pathway: Modulating anticancer immune response. J. Hematol. Oncol., 2017, 10(1), 101.
[http://dx.doi.org/10.1186/s13045-017-0471-6] [PMID: 28476164]
[20]
Ortuso, F.; Paduano, F.; Carotenuto, A.; Gomez-Monterrey, I.; Bilotta, A.; Gaudio, E.; Sala, M.; Artese, A.; Vernieri, E.; Dattilo, V.; Iuliano, R.; Brancaccio, D.; Bertamino, A.; Musella, S.; Alcaro, S.; Grieco, P.; Perrotti, N.; Croce, C.M.; Novellino, E.; Fusco, A.; Campiglia, P.; Trapasso, F. Discovery of PTPRJ agonist peptides that effectively inhibit in vitro cancer cell proliferation and tube formation. ACS Chem. Biol., 2013, 8(7), 1497-1506.
[http://dx.doi.org/10.1021/cb3007192] [PMID: 23627474]
[21]
Hass, C.S.; Lam, K.; Wold, M.S. Repair-specific functions of replication protein A. J. Biol. Chem., 2012, 287(6), 3908-3918.
[http://dx.doi.org/10.1074/jbc.M111.287441] [PMID: 22179778]
[22]
Kim, Y.E.; Won, M.; Lee, S.G.; Park, C.; Song, C.H.; Kim, K.K. RBM47-regulated alternative splicing of TJP1 promotes actin stress fiber assembly during epithelial-to-mesenchymal transition. Oncogene, 2019, 38(38), 6521-6536.
[http://dx.doi.org/10.1038/s41388-019-0892-5] [PMID: 31358901]

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