TOPOİZOMERAZ İNHİBİTÖRLERİ OLARAK BAZI BENZAMİD TÜREVLERİ ÜZERİNDE MOLEKÜLER DOKİNG ÇALIŞMALARI

Yıl 2020, Cilt: 44 Sayı: 3, 470 - 480, 30.09.2020

Serap Yilmaz , Sanaz Ataei İlkay Yıldız

https://doi.org/10.33483/jfpau.789537

Cited By: 1

Öz

Amaç: Antikanser aktivite göstereceği düşünülen Bazı benzamid türevlerinin insan Topo I ve IIα enzimleri ile moleküler düzeydeki etkileşimlerinin incelenmesi amacıyla bu enzimler üzerinden doking çalışmaları gerçekleştirilmiştir.

Gereç ve Yöntem: Doking çalışmalarının gerçekleştirilmesinde protein veri bankasından Topo I için (1K4T) ve Topo IIα için (5GWK) seçilmiştir, Discovery studio 3.5 programı kullanılarak CDocker yöntemiyle doking işlemi yapılmış ve benzamid türevlerinin enzimlere bağlanma enerjileri hesaplanmış ve moleküler etkileşimleri ortaya çıkartılmıştır.

Sonuç ve Tartışma: Topo I ve IIα üzerinden yapılan docking işlemi sonucunda benzamid türevi bileşiklerin Topo IIα enzimine afinitesinin daha yüksek olduğu bulunmuştur. 4N6, 5N5 bileşikleri Topo I; 5N3, 5N7 bileşikleri de Topo IIα inhbitörleri olarak antikanser aktivite göstermesi açısından umut verici bileşikler olarak belirlenmiştir.

Anahtar Kelimeler

Antikanser, Benzamid, Doking, Topoizomeraz I, Topoizomeraz IIα

MOLECULAR DOCKING STUDIES ON SOME BENZAMIDE DERIVATIVES AS TOPOISOMERASE INHIBITORS

Öz

Objective: In order to examine the interactions of some benzamide derivatives, which are thought to exhibit anti-cancer activity, with human Topo I and IIα enzymes at the molecular level, docking studies were carried out on these enzymes.

Material and Method: In conducting the docking studies, the protein was selected from the protein data bank for Topo I (1K4T) and for Topo IIα (5GWK). Doking was performed with the CDocker method using the Discovery studio 3.5 program, and the binding energies of benzamide derivatives to enzymes were calculated and their molecular interactions were revealed.

Result and Discussion: As a result of the docking process on Topo I and IIα, it was found that benzamide derivative compounds have higher affinity for Topo IIα enzyme. For Topo I compounds 4N6, 5N5; for Topo IIa compounds 5N3, 5N7 have been identified as promising compounds in terms of anticancer activity.

Anahtar Kelimeler

Anticancer, Benzamide, Docking, Topoisomerase I, Topoisomerase IIα

Kaynakça

• 1. Holden, J.A. (2001). DNA Topoisomerases as anticancer drug targets from the laboratory to the clinic. Current Medicinal Chemistry-Anti-Cancer Agents. 1(1), 1-25.
• 2. Topcu, Z. (2001). DNA topoisomerases as targets for anticancer drugs. Journal of clinical pharmacy and therapeutics. 26(6), 405-416.
• 3. Wang, J.C. (1996). DNA topoisomerases. Annual review of biochemistry. 65(1), 635-692.
• 4. Berger, J.M. (1998). Structure of DNA topoisomerases. Biochimica et Biophysica Acta (BBA)-Gene Structure and Expression. 1400 (1-3), 3-18.
• 5. Kaufmann, S.H. (1998). Cell death induced by topoisomerase-targeted drugs: more questions than answers. Biochimica et Biophysica Acta (BBA)-Gene Structure and Expression. 1400 (1-3), 195-211.
• 6. Pommier, Y. (1998). Diversity of DNA topoisomerases I and inhibitors. Biochimie. 80(3), 255-270.
• 7. Redinbo, M.R., Stewart, L., Kuhn, P., Champoux, J.J., Hol, W.G. (1998). Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science. 279 (5356), 1504-1513.
• 8. Cowell, I.G., Sondka, Z., Smith, K., Lee, K.C., Manville, C.M., Sidorczuk-Lesthuruge, M. , Rance, H.A., Padget, K., Jackson, G.H., Adachi, N. (2012). Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity. Proceedings of the National Academy of Sciences. 109(23), 8989-8994.
• 9. Wang, J.C.. (2002). Cellular roles of DNA topoisomerases: a molecular perspective. Nature reviews Molecular cell biology. 3(6), 430-440.
• 10. Pommier, Y., Leo, E., Zhang, H., Marchand, C. (2010). DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chemistry & biology. 17(5), 421-433.
• 11. Giovanella, B.C., Stehlin, J.S., Wall, M.E., Wani, M.C., Nicholas, A.W., Liu, L.F., Silber, R., Potmesil, M. (1989). DNA topoisomerase I--targeted chemotherapy of human colon cancer in xenografts. Science. 246(4933),1046-1048
• 12. Husain, I., Mohler, J.L., Seigler, H.F., Besterman, J.M. (1994). Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. Cancer research. 54(2), 539-546.
• 13. Lima, C.D., Wang, J.C., Mondragón, A. (1994). Three-dimensional structure of the 67K N-terminal fragment of E. coli DNA topoisomerase I. Nature. 367(6459), 138-146.
• 14. Garcia-Carbonero, R., Supko, J.G. (2002). Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clinical Cancer Research. 8(3), 641-661.
• 15. Wall, M.E., Wani, M.C., Cook, C., Palmer, K.H., McPhail, A.A., Sim, G. (1966). Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminata1, 2. Journal of the American Chemical Society. 88(16), 3888-3890.
• 16. Thomas, C.J., Rahier, N.J., Hecht, S.M. (2004). Camptothecin: current perspectives. Bioorganic & medicinal chemistry. 12(7), 1585-1604.
• 17. Teicher, B.A. (2008). Next generation topoisomerase I inhibitors: Rationale and biomarker strategies. Biochemical pharmacology. 75(6), 1262-1271.
• 18. Nitiss, J.L. (2009). DNA topoisomerase II and its growing repertoire of biological functions. Nature Reviews Cancer. 9(5), 327-337.
• 19. Pogorelcnik, B., Perdih, A., Solmajer, T. (2013). Recent advances in the development of catalytic inhibitors of human DNA topoisomerase IIα as novel anticancer agents. Current medicinal chemistry. 20, 694-709.
• 20. Schmidt, B.H., Osheroff, N., Berger, J.M. (2012). Structure of a topoisomerase II–DNA–nucleotide complex reveals a new control mechanism for ATPase activity. Nature structural & molecular biology. 19, 1147.
• 21. Larsen, A.K., Escargueil, A.E., Skladanowski, A. (2003). Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacology & therapeutics. 99, 167-181.
• 22. Farr, C.J., Antoniou-Kourounioti, M., Mimmack, M.L., Volkov, A., Porter, A.C. (2014). The α isoform of topoisomerase II is required for hypercompaction of mitotic chromosomes in human cells. Nucleic acids research. 42, 4414-4426.
• 23. Arcy, D. N., Gabrielli, B. (2017). Topoisomerase II inhibitors and poisons, and the influence of cell cycle checkpoints. Current Medicinal Chemistry. 24, 1504-1519.
• 24. McClendon, A.K., Rodriguez, A.C., Osheroff, N. (2005). Human topoisomerase IIα rapidly relaxes positively supercoiled DNA implications for enzyme action ahead of replication forks. Journal of Biological Chemistry. 280, 39337-39345.
• 25. Hande, K. (1998). Etoposide: four decades of development of a topoisomerase II inhibitor. European journal of cancer. 34, 1514-1521.
• 26. Zhang, J., Yang, P.L., Gray, N.S. (2009). Targeting cancer with small molecule kinase inhibitors. Nature Reviews Cancer. 9, 28-39.
• 27. Lu, A., Luo, H., Shi, M., Wu, G., Yuan, Y., Liu, J., Tang, F. (2011). Design, synthesis and docking studies on benzamide derivatives as histone deacetylase inhibitors. Bioorganic & medicinal chemistry letters. 21, 4924-4927.
• 28. Aboraia, A.S., Yee, S.W., Gomaa, M.S., Shah, N., Robotham, A.C., Makowski, B., Prosser, D., Brancale, A., Jones, G., Simons, C. (2010). Synthesis and CYP24A1 inhibitory activity of N-(2-(1H-imidazol-1-yl)-2-phenylethyl) arylamides. Bioorganic & medicinal chemistry. 18, 4939-4946.
• 29. Li, Y., Zhou, Y., Qian, P., Wang, Y., Jiang, F., Yao, Z., Hu, W., Zhao, Y., Li, S. (2013). Design, synthesis and bioevalution of novel benzamides derivatives as HDAC inhibitors. Bioorganic & medicinal chemistry letters. 23, 179-182.
• 30. Mao, W., et al., (2012). Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators. Bioorganic & medicinal chemistry. 20(9): p. 2982-2991.
• 31. Fiorino, F., Eiden, M., Giese, A., Severino, B., Esposito, A., Groschup, M.H., Perissutti, E., Magli, E., Incisivo, G.M., Ciano, A. (2012). Synthesis of benzamide derivatives and their evaluation as antiprion agents. Bioorganic & medicinal chemistry. 20, 5001-5011.
• 32. Kamal, A., Suresh, P., Ramaiah, M.J., Srinivasa Reddy, T., Kapavarapu, R.K., Rao, B.N., Imthiajali, S., Lakshminarayan Reddy, T., Pushpavalli, S.N.C.V.L., Shankaraiah, N., Pal-Bhadra, M. (2013). 4β-[4′-(1-(Aryl)ureido)benzamide] podophyllotoxins as DNA topoisomerase I and IIα inhibitors and apoptosis inducing agents. Bioorganic & Medicinal Chemistry. 21, 5198-5208.
• 33. Kamal, A., Suresh, P., Ramaiah, M.J., Mallareddy, A., Imthiajali, S., Pushpavalli, S.N.C.V.L., Lavanya, A., Pal-Bhadra, M. (2012). Synthesis and biological evaluation of 4β-sulphonamido and 4β-[(4′-sulphonamido)benzamide]podophyllotoxins as DNA topoisomerase-IIα and apoptosis inducing agents. Bioorganic & Medicinal Chemistry. 20, 2054-2066.
• 34. Acar, C., Yalcin, G., Ertan-Bolelli, T., Onurdag, F.K., Okten, S., Sener, F., Yildiz, I. (2020). Synthesis and molecular docking studies of some novel antimicrobial benzamides. Bioorganic Chemistry. 94, 103368.
• 35. Wendorff, T.J., Schmidt, B.H., Heslop, P., Austin, C.A., Berger, J.M. (2012). The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. Journal of molecular biology. 424, 109-124.
• 36. Wang, Y.-R., Chen, S.-F., Wu, C.-C., Liao, Y.-W., Lin, T.-S., Liu, K.-T., Chen, Y.-S., Li, T.-K., Chien, T.-C., Chan, N.-L. (2017). Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt (II)-methionine coordination chemistry. Nucleic acids research. 45, 10861-10871.
• 37. Accelrys, Discovery Studio 3.5 2012.
• 38. Momany, F.A., Rone, R. (1992). Validation of the general purpose QUANTA® 3.2/CHARMm® force field. Journal of Computational Chemistry. 13, 888-900.
• 39. Crisfield, M. (1979). A faster modified Newton-Raphson iteration. Computer Methods in Applied Mechanics and Engineering. 20, 267-278.
• 40. Wu, G., Robertson, D.H., Brooks III, C.L., Vieth, M. (2003). Detailed analysis of grid‐based molecular docking: A case study of CDOCKER—A CHARMm‐based MD docking algorithm. Journal of computational chemistry. 24, 1549-1562.