COMPUTERISED DESIGNING OF DOXORUBICIN WITH BREAST CANCER CELLS

Öz

Objective: Breast cancer is the type of cancer that starts in breast cells and has the highest incidence in the world after lung cancer. Doxorubicin is widely used in the treatment of some leukemia and Hodgkin’s lymphoma, as well as in the treatment of bladder, breast, stomach, lung, ovary, thyroid, soft tissue sarcoma, multiple myeloma and other cancers. We want to determine the binding interaction of Doxorubicin in the active site of the Galectin-3 with ASN-48, ARG-32, ASN-62 and GLU-72 residues, conformation and docking score energies.

Material and Method:  We used docking methods to detect the efficiency of Doxorubicin at breast cancer cells, clarify the role of Galectin-3 and elucidate the interaction between Galectin-3 and Doxorubicin.

Results:  The docking score obtained for Doxorubicin in the active side of the Galectin-3 protein was -5.32 kcal/mol. In to the active site of protein, Doxorubicin was bound with strong hydrogen bond by the residue ASN-48, ARG-32, ASN-62 and GLU-72, and a salt bridge with the same amino acid residue were established and stability was achieved. 

Conclusion: The development of specific therapies targeting cancer stem cells may provide hope for prolonging the life span and improving quality.

Anahtar Kelimeler

• Docking,breast cancer,Galectin-3,Doxorubicin

DOKSORUBİSİNİN MEME KANSERİ HÜCRELERİ İLE BİLGİSAYARLI TASARIMI

Öz

Amaç: Meme kanseri, meme hücrelerinde başlayan ve akciğer kanserinden sonra dünyada en yüksek insidansa sahip olan kanser türüdür. Doksorubisin, bazı lösemi ve Hodgkin lenfomasının yanı sıra mesane, meme, mide, akciğer, yumurtalık, tiroid, yumuşak doku sarkomu, multipl miyeloma ve diğer kanserlerin tedavisinde yaygın olarak kullanılır. Çalışmamızda; Doksorubisin’in Galektin 3’ün aktif bölgesinde yer alan, ASN-48, ARG-32, ASN-62 ve GLU-72 rezidüleri ile yaptığı bağlanma etkileşimlerini, konformasyonlarını ve doking skor enerjilerini belirlemek istedik.

Gereç ve Yöntem: Meme kanseri hücrelerinde Doxorubicin etkinliğini tespit etmek, Galectin-3 rolünü netleştirmek ve Galektin-3 ve Doksorubisin arasındaki etkileşimi aydınlatmak için doking yöntemi kullanılmıştır.

Bulgular: Tüm konformerler arasında Doksorubisin Galektin-3  proteini ile en iyi kenetlenme sonucunu -5,32 kcal/mol docking skoruna sahip konformer vermiştir. Doksorubisin güçlü hidrojen bağları ile ASN-48, ARG-32, ASN-62 ve GLU-72 rezidülerine bağlanmış ve aynı amino asit rezidüleri ile bir tuz köprüsü de kurarak, kararlılık sağlanmıştır.

Sonuç: Kanser kök hücrelerini hedef alan spesifik tedavilerin geliştirilmesi açısından, yaşam süresinin uzatılması ve kalitenin arttırılması için bu çalışmanın umut sağlayabilir olduğunu düşünmekteyiz.

Anahtar Kelimeler

• Doking,meme kanseri,Galektin-3,doksorubisin

Kaynakça

1. 1. Lovitt CJ, Shelper TB, Avery, VM. Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins. BMC Cancer 2018;18(1):41.
2. 2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(2):69-90.
3. 3. Demark-Wahnefried W, Campbell KL, Hayes SC. Weight management and its role in breast cancer rehabilitation. Cancer 2012;118(Suppl. 8):2277-87.
4. 4. Pierce JP, Stefanick ML, Flatt SW, Natarajan L, Sternfeld B, Madlensky L, et al. Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol 2007;25(17):2345-51.
5. 5. Gonzales JF, Barnard ND, Jenkins DJ, Lanou AJ, Davis B, Saxe G, Levin S. Applying the precautionary principle to nutrition and cancer. J Am Coll Nutr 2014;33(3):239-46.
6. 6. Bodai BI, Tuso P. Breast cancer survivorship: a comprehensive review of long-term medical issues and lifestyle recommendations. Perm J 2015;19(2):48-79.
7. 7. Kontoyannis A, Sweetland H. Adjuvant therapy for breast cancer. Surgery (Oxford) 2007;25(6):272-5.
8. 8. Hernandez-Aya LF, Gonzalez-Angulo AM. Adjuvant systemic therapies in breast cancer. Surg Clin North Am 2013;93(2):473-91.

9. 9. Berman, AT, Thukral AD, Hwang WT, Solin LJ, Vapiwala N. Incidence and patterns of distant metastases for patients with early-stage breast cancer after breast conservation treatment. Clin Breast Cancer 2013;13(2):88-94.
10. 10. Carvalho C, Santos RX, Cardoso S, Correia S, Oliveira PJ, Santos MS, et al. Doxorubicin: the good, the bad and the ugly effect. Curr med Chem 2009;16(25):3267-85.
11. 11. Arcamone F, Cassinelli G, Fantini G, Grein A, Oerezzi P, Pol C, et al. Adriamycin, 14-hydroxydaimomycin, a new antitumor antibiotic from S. Peucetius var. caesius. Biotechno Bioeng 1969;11(6):1101-10.
12. 12. Cortés-Funes H, Coronado C. Role of anthracyclines in the era of targeted therapy. Cardiovasc Toxicol 2007;7(2):56-60.
13. 13. Weiss RB, The anthracyclines: will we ever find a better doxorubicin? In: Seminars in oncology. Elsevier 1992: p. 670-86.
14. 14. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003;97(11):2869-79.
15. 15. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenetics and Genomics 2011;21(7):440-6.
16. 16. Hsu DK, Liu FT. Regulation of cellular homeostasis by galectins. Glycoconj J 2002;19(7-9):507-15.
17. 17. Choi JH, Chun KH, Raz A, Lotan R. Inhibition of N-(4-hydroxyphenyl) retinamide-induced apoptosis in breast cancer cells by galectin-3. Cancer Biol Ther 2004;3(5):447-52.
18. 18. Takenaka Y, Fukumori T, Yoshii T, Oka N, Inohara H, Kim HR, et al. Nuclear export of phosphorylated galectin-3 regulates its antiapoptotic activity in response to chemotherapeutic drugs. J Mol Sci 2004;24(10):4395-406.
19. 19. Meng Xuan-Yu, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des 2011;7(2):146-57.
20. 20. McConkey BJ, Sobolev V, Edelman M. The performance of current methods in ligand–protein docking. Curr Sci 2002;83(7):845-56.
21. 21. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein− ligand complexes. J Med Chem 2006;49(21):6177-96.
22. 22. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, et al. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 2004;47(7):1750-9.
23. 23. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004;47(7):1739-49.
24. 24. Harder E, Damm W, Maple J, Wu C, Reboul M, Yu Xiang J, et al. OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput 2015;12(1):281-96.
25. 25. Guha P, Bandyopadhyaya G, Polumuri SK, Chumsri S, Gade P, Kalvakolanu DV, et al. Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, α9 nicotinic acetylcholine receptor and STAT3. Breast Cancer Res Treat 2014;145(1):5-22.
26. 26. Bienert S, Waterhouse A, de Beer, Tjaart A. P. Tauriello G, Studer G, Bordoli L et al. The SWISS-MODEL Repository—new features and functionality. Nucleic Acids Res 2016;45(D1):D313-D319.
27. 27. Søndergaard CR, Olsson MH, Rostkowski M, Jensen JH. Improved treatment of ligands and coupling effects in empirical calculation and rationalization of pKa values. J Chem Theory Comput 2011;7(7):2284-95.
28. 28. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Computer-Aided Mol Design 2013;27(3):221-34.
29. 29. Oprea TI, Gottfries J. Toward minimalistic modeling of oral drug absorption. J Mol Graph Model 1999;17(5-6): 61-74.