In-vitro Cytotoxicity and In-silico Insights of the Multi-target Anticancer Candidates from Haplophyllum tuberculatum
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Submitted
29 December 2020
Published
30 August 2021
Keywords:
-
Anticancer, Molecular docking, Target identification, Drug-likeness, Polygamain, Justicidin A
Abstract
This study aimed to investigate the anticancer activity of Haplophyllum tuberculatum(Forsk.) aerial parts ethanol extract and fractions and reveal the potential anticancer targets, binding modes, pharmacokinetics, and toxicity properties of its phytoconstituents. MTT assay was used to investigate the anticancer activity. TargetNet, ChemProt version 2.0, and CLC-Pred web servers were used for virtual screening, and Cresset Flare software was used for molecular docking with the 26 predicted targets. Moreover, pkCSM, swiss ADME, and eMolTox web servers were used to predict pharmacokinetics and safety. Ethanolic extracts of H. tuberculatum on HepG2 and HeLa cell lines showed promising activities with IC50 values 54.12 and 48.1 µg/mL, respectively. Further, ethyl acetate fraction showed the highest cytotoxicity on HepG2 and HeLa cell lines with IC50 values 41.7 and 52.31 µg/mL. Of 70 compounds screened virtually, polygamain, justicidin A, justicidin B, haplotubine, kusunokinin, and flindersine were predicted as safe anticancer drugs candidates. They showed the highest binding scores with targets involved in cell growth, proliferation, survival, migration, tumor suppression, induction of apoptosis, metastasis, and drug resistance. Our findings revealed the potency of H. tuberculatum as a source of anticancer candidates that further studies should support.
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References
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26. Ibrahim MM, Elsaman T, Al-Nour MY. Synthesis, Anti-Inflammatory Activity, and In Silico Study of Novel Diclofenac and Isatin Conjugates. Int J Med Chem. 2018;2018:9139786. doi:10.1155/2018/9139786
27. Pantsar T, Poso A. Binding Affinity via Docking: Fact and Fiction. Molecules. 2018;23(8):1899. doi:10.3390/molecules23081899
28. Peng J, Hartley RM, Fest GA, Mooberry SL. Amyrisins A-C, O-prenylated flavonoids from Amyris madrensis. J Nat Prod. 2012;75(3):494-6. doi:10.1021/np200796e
29. Momekov G, Konstantinov S, Dineva I, Ionkova I. Effect of justicidin B - a potent cytotoxic and pro-apoptotic arylnaphtalene lignan on human breast cancer-derived cell lines. Neoplasma. 2011;58(4):320-5. doi:10.4149/neo_2011_04_320
30. Momekov G, Yossifov D, Guenova M, Michova A, Stoyanov N, Konstantinov S, et al. Apoptotic mechanisms of the biotechnologically produced arylnaphtalene lignan justicidin B in the acute myeloid leukemia-derived cell line HL-60. Pharmacol Rep. 2014;66(6):1073-6. doi:10.1016/j.pharep.2014.07.005
2. Nurgali K, Jagoe RT, Abalo R. Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae? Front Pharmacol. 2018;9:245. doi:10.3389/fphar.2018.00245
3. Rayan A, Raiyn J, Falah M. Nature is the best source of anticancer drugs: Indexing natural products for their anticancer bioactivity. PLoS One. 2017;12(11):e0187925. doi:10.1371/journal.pone.0187925
4. Hamdi A, Bero J, Beaufay C, Flamini G, Marzouk Z, Heyden YV, et al. In vitro antileishmanial and cytotoxicity activities of essential oils from Haplophyllum tuberculatum A. Juss leaves, stems and aerial parts. BMC Complement Altern Med. 2018;18(1):60. doi:10.1186/s12906-018-2128-6
5. Eissa TF, González-Burgos E, Carretero ME, Gómez-Serranillos MP. Biological activity of HPLC-characterized ethanol extract from the aerial parts of Haplophyllum tuberculatum. Pharm Biol. 2014;52(5):151-6. doi:10.3109/13880209.2013.819517
6. Al-Snafi AE. Pharmacological importance of Haplophyllum species grown in Iraq- A review. IOSR J Pharm. 2018;8(5):54-62.
7. Al-Rehaily AJ, Al-Howiriny TA, Ahmad MS, Al-Yahya MA, El-Feraly FS, Hufford CD, et al. Alkaloids from Haplophyllum tuberculatum. Phytochemistry. 2001;57(4):597-602. doi:10.1016/s0031-9422(01)00041-3
8. Sheriha GM, Amer KMA. Lignans of haplophyllum tuberculatum. Phytochemistry. 1984;23(1):151-3. doi:10.1016/0031-9422(84)83096-4
9. Aberrane A, Djouahri A, Djerrad Z, Saka B, Benseradj F, Aitmoussa S, et al. Changes in essential oil composition of Haplophyllum tuberculatum (Forssk.) A. Juss. aerial parts according to the developmental stage of growth and incidence on the biological activities. J Essent Oil Res. 2019;31(1):69-89. doi:10.1080/10412905.2018.1511483
10. Khalid SA, Waterman PG. Alkaloid, lignan and flavonoid constituents of Haplophyllum tuberculatum from Sudan. Planta Med. 1981;43(2):148-52. doi:10.1055/s-2007-971491
11. Jones LH. An industry perspective on drug target validation. Expert Opin Drug Discov. 2016;11(7):623-5. doi:10.1080/17460441.2016.1182484
12. Al-Nour MY, Ibrahim MM, Elsaman T. Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action. Curr Pharmacol Rep. 2019;5:255-80. doi:10.1007/s40495-019-00181-w
13. Kumar P, Nagarajan A, Uchil PD. Analysis of Cell Viability by the MTT Assay. Cold Spring Harb Protoc. 2018;2018(6). doi:10.1101/pdb.prot095505
14. Arbab AH, Parvez MK, Al-Dosari MS, Al-Rehaily AJ, Ibrahim KE, Alam P, et al. Therapeutic efficacy of ethanolic extract of Aerva javanica aerial parts in the amelioration of CCl4-induced hepatotoxicity and oxidative damage in rats. Food Nutr Res. 2016;60: 30864. doi:10.3402/fnr.v60.30864
15. Lagunin A, Stepanchikova A, Filimonov D, Poroikov V. PASS: prediction of activity spectra for biologically active substances. Bioinformatics. 2000;16(8):747-8. doi:10.1093/bioinformatics/16.8.747
16. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717. doi:10.1038/srep42717
17. Cheeseright T, Mackey M, Rose S, Vinter A. Molecular field extrema as descriptors of biological activity: definition and validation. J Chem Inf Model. 2006;46(2):665-76. doi:10.1021/ci050357s
18. Yao ZJ, Dong J, Che YJ, Zhu MF, Wen M, Wang NN, et al. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models. J Comput Aided Mol Des. 2016;30(5):413-24. doi:10.1007/s10822-016-9915-2
19. Kjærulff SK, Wich L, Kringelum J, Jacobsen UP, Kouskoumvekaki I, Audouze K, et al. ChemProt-2.0: visual navigation in a disease chemical biology database. Nucleic Acids Res. 2013;41(Database issue):D464-9. doi:10.1093/nar/gks1166
20. Lagunin AA, Dubovskaja VI, Rudik AV, Pogodin PV, Druzhilovskiy DS, Gloriozova TA, et al. CLC-Pred: A freely available web-service for in silico prediction of human cell line cytotoxicity for drug-like compounds. PLoS One. 2018;13(1):e0191838. doi:10.1371/journal.pone.0191838
21. Bernstein FC, Koetzle TF, Williams GJ, Meyer Jr EF, Brice MD, Rodgers JR, et al. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977;112(3):535-42. doi:10.1016/s0022-2836(77)80200-3
22. Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J Med Chem. 2015;58(9):4066-72. doi:10.1021/acs.jmedchem.5b00104
23. Mahajan P, Wadhwa B, Barik MR, Malik F, Nargotra A. Combining ligand- and structure-based in silico methods for the identification of natural product-based inhibitors of Akt1. Mol Divers. 2020;24(1):45-60. doi:10.1007/s11030-019-09924-9
24. Pereira F, Aires-de-Sousa J. Computational Methodologies in the Exploration of Marine Natural Product Leads. Mar Drugs. 2018;16(7):236. doi:10.3390/md16070236
25. Prachayasittikul V, Worachartcheewan A, Shoombuatong W, Songtawee N, Simeon S, Prachayasittikul V, et al. Computer-Aided Drug Design of Bioactive Natural Products. Curr Top Med Chem. 2015;15(18):1780-800. doi:10.2174/1568026615666150506151101
26. Ibrahim MM, Elsaman T, Al-Nour MY. Synthesis, Anti-Inflammatory Activity, and In Silico Study of Novel Diclofenac and Isatin Conjugates. Int J Med Chem. 2018;2018:9139786. doi:10.1155/2018/9139786
27. Pantsar T, Poso A. Binding Affinity via Docking: Fact and Fiction. Molecules. 2018;23(8):1899. doi:10.3390/molecules23081899
28. Peng J, Hartley RM, Fest GA, Mooberry SL. Amyrisins A-C, O-prenylated flavonoids from Amyris madrensis. J Nat Prod. 2012;75(3):494-6. doi:10.1021/np200796e
29. Momekov G, Konstantinov S, Dineva I, Ionkova I. Effect of justicidin B - a potent cytotoxic and pro-apoptotic arylnaphtalene lignan on human breast cancer-derived cell lines. Neoplasma. 2011;58(4):320-5. doi:10.4149/neo_2011_04_320
30. Momekov G, Yossifov D, Guenova M, Michova A, Stoyanov N, Konstantinov S, et al. Apoptotic mechanisms of the biotechnologically produced arylnaphtalene lignan justicidin B in the acute myeloid leukemia-derived cell line HL-60. Pharmacol Rep. 2014;66(6):1073-6. doi:10.1016/j.pharep.2014.07.005
Authors
1.
Al-Nour MY, Arbab AH, Parvez MK, Mohamed AY, Al-Dosari MS. In-vitro Cytotoxicity and In-silico Insights of the Multi-target Anticancer Candidates from Haplophyllum tuberculatum. Borneo J Pharm [Internet]. 2021Aug.30 [cited 2024Apr.18];4(3):192-201. Available from: https://journal.umpr.ac.id/index.php/bjop/article/view/1955
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