IN SILICO DOCKING STUDIES ON THE ANTI-CANCER EFFECT OF THYMOQUINONE ON INTERACTION WITH PTEN- A REGULATOR OF PI3K/ AKT PATHWAY
Objective: The statistics on cancer imposes the urge to extend new methods to control this deadly form of the disease. Phosphatase and tensin
homolog located on chromosome 10q23 (PTEN) is inactivated in a subset and AKT is frequently activated in cancer. The PTEN is the central negative
regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling cascade that influences multiple cellular functions including cell growth, survival,
proliferation and migration in a context-dependent manner. Dysregulation of this signaling pathway contributes to different types of cancers. The
objective of the study is to explore the anti-cancer potential of thymoquinone (TQ) by analyzing the interaction between TQ with the target protein
Methods: The three dimensional structure of TQ is designed using in-silico methods, and the structure of PTEN is obtained from National Center for
Biotechnology Information against protein data bank. The query sequence from 8 to 353 amino acids was found to be 85% homologous to ID5R. For
the target protein PTEN with 403 residues, protein families analysis covered the important domains in PTEN.
Result: TQ showed the binding energy of âˆ’7.37 Kcal/mol against PTEN with three hydrogen bonds.
Conclusion: Present study suggests that TQ might inhibit abnormal cell proliferation occurring in cancer by modulating the activity of PTEN,
a negative regulator of PI3K/AKT pathway.
Keywords: Cancer, Thymoquinone, Phosphatase and tensin homolog located on chromosome 10q23, Docking and hydrogen bonds.
2. Rafter JJ. Scientific basis of biomarkers and benefits of functional foods for reduction of disease risk: Cancer. Br J Nutr 2002;88 Suppl 2:S219â€‘24.
3. Loo G. Redox-sensitive mechanisms of phytochemical-mediated inhibition of cancer cell proliferation review. J Nutr Biochem 2003;14(2):64-73.
4. Kwon KH, Barve A, Yu S, Huang MT, Kong AN. Cancer chemoprevention by phytochemicals: Potential molecular targets, biomarkers and animal models. Acta Pharmacol Sin 2007;28(9):1409â€‘21.
5. Guldberg P, Thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 1997;57(17):3660â€‘3.
6. Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG, et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 1997;57(22):4997-5000.
7. Kohno T, Takahashi M, Manda R, Yokota J. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer 1998;22(2):152-6.
8. Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 1997;57(18):3935â€‘40.
9. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997;16(1):64-7.
10. Stewart AL, Mhashilkar AM, Yang XH, Ekmekcioglu S, Saito Y, Sieger K, et al. PI3 kinase blockade by Ad-PTEN inhibits invasion and induces apoptosis in RGP and metastatic melanoma cells. Mol Med 2002;8(8):451-61.
11. Tang JM, He QY, Guo RX, Chang XJ. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer 2006;51(2):181-91.
12. Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK, et al. PTEN expression in non-small-cell lung cancer: Evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 2005;36(7):768-76.
13. Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J 2003;22(20):5501-10.
14. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Sci 1998;280(5369):1614-7.
15. Castellino RC, Durden DL. Mechanisms of disease: The PI3K-Akt-PTEN signaling node â€“ An intercept point for the control of angiogenesis in brain tumors. Nat Clin Pract Neurol 2007;3(12):682-93.
16. Srinivasan P, Sudha A, Hameed AS, Prasanth Kumar S, Karthikeyan M. Screening of medicinal plant compounds against NS5B polymerase of hepatitis C virus (HCV) using molecular docking studies. J Pharm Res 2011;4:136-40.
17. Massion PP, Taflan PM, Shyr Y, Rahman SM, Yildiz P, Shakthour B, et al. Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am J Respir Crit Care Med 2004;170:1088â€‘94.
18. Gali-Muhtasib HU, Abou Kheir WG, Kheir LA, Darwiche N, Crooks PA. Molecular pathway for thymoquinone-induced cell-cycle arrest and apoptosis in neoplastic keratinocytes. Anticancer Drugs 2004;15(4):389-99.
19. Salem ML. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int Immunopharmacol 2005;5(13-14):1749-70.
20. El-Mahdy MA, Zhu Q, Wang QE, Wani G, Wani AA. Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells. Int J Cancer 2005;117:409-17.
21. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The Protein Data Bank. Nucleic Acids Res 2000;28(1):235-42.
22. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A 2002;99(26):16899-903.
23. Pearson WR, Lipman DJ. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A 1988;85(8):2444-8.
24. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol 1990;215(3):403-10.
25. Finn RD, Mistry J, Tate J, Coggill P, Heger A, Pollington JE, et al. The Pfam protein families database. Nucleic Acids Res 2010;38(Database issue):D211-22.
26. Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, Shen MY, et al. Comparative protein structure modeling using Modeller. Curr Protoc Bioinformatics 2006;Chapter 5:Unit 5.6.
27. Shindyalov IN, Bourne PE. Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. Protein Eng 1998;11(9):739-47.
28. James A, Perkins A. History of molecular representation Part 2: The 1960s - Present. J Biocommun 2005;31. Available from: http://www.accelrys.com/viewer/viewerlite.
29. Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis 1997;18(15):2714-23.
30. Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK - A program to check the stereochemical quality of protein structures. J App Cryst 1993;26:283-91. Available from: htttp://www.nih.mbi.ucla.edu.
31. Laurie AT, Jackson RM. Q-SiteFinder: An energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 2005;21(9):1908-16.
32. Brooijmans N, Kuntz ID. Molecular recognition and docking algorithms. Annu Rev Biophys Biomol Struct 2003;32:335-73.
33. Irwin J, Lorber DM, McGovern SL, Wei B, Shoichet BK. Docking and drug discovery. In: Technical Proceedings of the International Conference on Computational Nanoscience and Nanotechnology: Computer Aided Drug Design, Northwestern University US, Nanotech. Vol. 2. 2002. p. 50-1.
34. Johnson DE, Wolfgang GH. Predicting human safety: Screening and computational approaches. Drug Discov Today 2000;5:445-54.
35. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46(1-3):3-26.
36. Inbathamizh L, Padmini E. In silico studies on the inhibitory effects of calcitriol and 5, 5â€™dithiobis -2-nitrobenzoic acid on human glucosaminyl n-acetyl transferase 1 activity. Asian J Exp Biol Sci 2012;3(1):14-21.
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