TARGETING NUCLEAR FACTOR KAPPA B WITH CHELATED ZINC COMPOUNDS TOWARDS ANTICANCER DRUG DESIGN

  • NAGALAKSHMI K. VRR Institute of Biomedical Science, Kattupakkam, Chennai 600056, India
  • SHILA S. VRR Institute of Biomedical Science, Kattupakkam, Chennai 600056, India
  • INBATHAMIZH L. Department of Biotechnology, Sathyabama Institute of Science and Technology, Chennai-119
  • THENMOZHI A. Department of Biochemistry, SRM College of Arts and Science, Kattankulathur, Kanchipuram 603203, India
  • RASAPPAN P.
  • SRINIVASAN P. T. Department of Biochemistry, DG Vaishnav College, Arumbakkam, Chennai 600106, India

Abstract

Objective: The objective of the study was to analyse the target - ligand interactions between Nuclear factor-κB (NF-κB) and chelated Zinc compounds and to explore the anticancer drug potential of these ligands by a bio computational approach.


 


Methods: Bioinformatics databases and tools were applied for the study. Three dimensional structure of the target NF-κB was retrieved from Protein Data Bank (PDB). The optimized structures of two chelated Zinc compounds, Zinc acetate and Zinc orotate were taken for docking studies with the target using docking tool AutoDock 4.2. Drug properties of the ligands were further assessed by Molinspiration server.


 


Results: Docking results as predicted by AutoDock and as visualized by PyMol viewer were effective for both the ligands. Comparatively, Zinc orotate showed minimum energy and more interactions with the target. Both the ligands satisfied the Lipinsky’s rule of five with zero violations.


 


Conclusion: The findings emphasized the promising role of chelated Zinc compounds as potent drug candidates in anti-cancer drug design against NF-κB.

Keywords: NF-κB, Chelated Zinc, Bioinformatics, Docking, Drug-design

References

1. Gammoh NZ, Rink L. Zinc in Infection and In?ammation. Nutrients 2017;9(6):624.
2. Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor- ?B: Its role in health and disease. J Mol Med 2004;82:434-448.
3. Tergaonkar V. NF-?B pathway: A good signaling paradigm and therapeutic target. Int J Biochem Cell Biol 2006;38:1647-1653.
4. Zingarelli B. Nuclear factor-B. Crit Care Med 2005;33:S414-S416.
5. Xia Y, Shen S, Verma IM. NF-?B, an active player in human cancers. Cancer immunol Res 2014;2(9):823-830.
6. Ghosh S, Karin M. Missing pieces in the NF-?B puzzle. Cell 2002;109:S81–S96.
7. Jarosz M, Olbert M, Wyszogrodzka G, Mlyniec K, Librowski T. Antioxidant and anti-in?ammatory effects of zinc. Zinc-dependent NF-?B signaling. In?ammopharmacology 2017;25:11-24.
8. Meylan E, Dooley AL, Feldser DM, Shen L, Turk E, Ouyang C, et al. Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature 2009;462:104-107.
9. Xia Y, Yeddula N, Leblanc M, Ke E, Zhang Y, Oldfield E, et al. Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nat Cell Biol 2012;14:257-265.
10. Basseres DS, Ebbs A, Levantini E, Baldwin AS. Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis. Cancer Res 2010;70:3537-346.
11. Faa G, Nurchi VM, Ravarino A, Fanni D, Nemolato S, Gerosa C et al. Zinc in gastrointestinal and liver disease. Coord Chem Rev 2008;252:1257-1269.
12. Fukada T. Zinc biology and zinc signaling. Biomed Res Trace Elem 2015;26:1-6.
13. Zastrow ML, Pecoraro VL. Designing Hydrolytic Zinc Metalloenzymes. Biochemistry 2014;53:957-978.
14. Hasan R, Rink L, Haase H. Chelation of Free Zn2+ Impairs Chemotaxis, Phagocytosis, Oxidative Burst, Degranulation, and Cytokine Production by Neutrophil Granulocytes. Biol Trace Elem Res 2016;171:79-88.
15. Oteiza PI. Zinc and the modulation of redox homeostasis. Free Radic Biol Med 2012;53:1748-1759.
16. Krishna SS, Majumdar I, Grishin NV. Structural classi?cation of zinc ?ngers: Survey and summary. Nucleic Acids Res 2003;31:532-550.
17. Stepien M, Hughes DJ, Hybsier S, Bamia C, Tjønneland A, Overvad K et al. Circulating copper and zinc levels and risk of hepatobiliary cancers in Europeans. Br J Cancer 2017;116:688-696.
18. Kumar R, Razab S, Prabhu K, Ray S, Prakash B. Serum butyrylcholinesterase and zinc in breast cancer. J Cancer Res Ther 2017;13:367-370.
19. Khoshdel Z, Naghibalhossaini F, Abdollahi K, Shojaei S, Moradi MS, Malekzadeh M. Serum Copper and Zinc Levels Among Iranian Colorectal Cancer Patients. Biol Trace Elem Res 2015;170, 294-299.
20. Okunade KS, Dawodu OO, Salako O, Osanyin GE, Okunowo AA, Anorlu RI. Comparative analysis of serum trace element levels in women with invasive cervical cancer in Lagos, Nigeria. Pan Afr Med J 2018;31:194.
21. Zablocka-Slowinska K, Placzkowska S, Prescha A, Pawelczyk K, Porebska I, Kosacka M et al. Serum and whole blood Zn, Cu and Mn pro?les and their relation to redox status in lung cancer patients. J Trace Elem Med Biol 2018;45:78-84.
22. Wang Y, Sun Z, Li A, Zhang Y. Association between serum zinc levels and lung cancer: A meta-analysis of observational studies. World J Surg Oncol 2019;17(1):1-8.
23. Emami A, Nazem MR, Shekarriz R, Hedayati M. Micronutrient status (calcium, zinc, vitamins D and E) in patients with medullary thyroid carcinoma: A cross-sectional study. Nutrition 2017;41:86-89.
24. Lu H, Cai L, Mu LN, Lu QY, Zhao J, Cui Y et al. Dietary mineral and trace element intake and squamous cell carcinoma of the esophagus in a Chinese population. Nutr Cancer 2006;55:63-70.
25. Bidoli E, Bosetti C, La Vecchia C, Levi F, Parpinel M, Talamini R et al. Micronutrients and laryngeal cancer risk in Italy and Switzerland: A case-control study. Cancer Causes Control 2003;14:477-484.
26. Dhawan DK, Chadha VD. Zinc: A promising agent in dietary chemoprevention of cancer. Indian J Med Res 2010;132:676-682.
27. Lin S, Lin X, Yang Y, Li F, Luo L. Comparison of chelated zinc and zinc sulfate as zinc sources for growth and immune response of shrimp (Litopenaeus vannamei). Aquaculture 2013;406:79-84.
28. Sandstead HH, Prasad AS, Penland JG, Beck FWJ, Kaplan J, Egger NG, et al. Zinc de?ciency in Mexican American children: In?uence of zinc and other micronutrients on T cells, cytokines, and antiin?ammatory plasma proteins. Am J Clin Nutr 2008;88:1067-1073.
29. Kagara N, Tanaka N, Noguchi S, Hirano T. Zinc and its transporter ZIP10 are involved in invasive behavior of breast cancer cells. Cancer Sci 2007;98:692-697.
30. Morris GM, Goodsell DS, Halliday RS, et al. Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998;19:1639-62.
31. Blum C, Roli A, Sampels M. Hybrid metaheuristics: An emerging approach to optimization. Springer; 2008.
32. DeLano WL. The PyMOL Molecular Graphics System. San Carlos: DeLano Scientific; 2002.
33. Jarrahpour A, Fathi J, Mimouni M, Ben Hadda T, Sheikh J, Chohan Z, et al. Petra, Osiris and Molinspiration (POM) together as a successful support in drug design: antibacterial activity and biopharmaceutical characterization of some azo Schiff bases. Med Chem Res 2012;21:1984-1990.
34. Lipinski CA. Lead-and drug-like compounds: The rule-of-five revolution. Drug Discov Today Technol 2004;1:337-341.
35. Wang R, Lu Y, Wang S. Comparative evaluation of 11 scoring functions for molecular docking. J Med Chem 2003;46:2287-2303.
36. Inbathamizh L, Shyamala Devi K, Sri Vaishnavi Taarikaa S, Mithula P, Vennela KN. Targeting Cytochrome P450 1A1 Enzyme with Crucifer Phytocomponents: An In Silico Approach for Chemopreventive Drug Design against Lung Cancer. Asian J Pharm 2020;14(1):51-57.
37. Inbathamizh L, Padmini E. Quinic acid as a potent drug candidate for prostate cancer. Asian J Pharm Clin Res 2013;6:106-112.
38. Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 2007;6:881-890.
39. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002;45:2615-2623.
40. Ke H. Implications of PDE4 structure on inhibitor selectivity across PDE families. Int J Impot Res 2004;16(1):S24-S27.
41. Lemberger T, Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: A nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol 1996;12:335-363.
42. Strange RW, Antonyuk S, Hough MA, Doucette PA, Rodriguez JA, Hart PJ et al. The structure of holo and metal-de?cient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis. J Mol Biol 2003;328:877-891.
43. Zelko IN, Mariani TJ, Folz, RJ. Superoxide dismutase multigene family: A comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 2002;33:337-349.
44. John E, Laskow TC, Buchser WJ, Pitt BR, Basse PH, Butter?eld LH et al. Zinc in innate and adaptive tumor immunity. J Transl Med 2010;8:118.
Statistics
6 Views | Downloads
Citations
How to Cite
K., N., S., S., L., I., A., T., P., R., & P. T., S. (2021). TARGETING NUCLEAR FACTOR KAPPA B WITH CHELATED ZINC COMPOUNDS TOWARDS ANTICANCER DRUG DESIGN. International Journal of Applied Pharmaceutics, 13(4). https://doi.org/10.22159/ijap.2021v13i4.41650
Section
Original Article(s)