1. Introduction
Tamoxifen is a group of drugs of selective estrogen receptor modulators. Moreover, it is effective in preventing and treating some cancers (e.g., breast cancer). This study experimentally explored the interaction of tamoxifen with DNA. Moreover, the electronic structure (at the atomic scale) of the molecular system of tamoxifen was theoretically investigated, using Atom in Molecule (AIM) and Natural Bond Orbital (NBO) theories.
2. Materials & Methods
 In the experimental section, using the ct-DNA and Tris buffer and other solution and materials, the interaction of Tamoxifen with DNA was investigated by UV-ViS technique and hydrodynamic method (Viscometry). Then, in the theoretical part of this research, using computational biophysical chemistry methods, some properties of tamoxifen molecular system, such as electronic Density of States (DOS), Boundary Orbital’s Energy (HOMO/LUMO), Electrostatic Potential Energy (EPS), and the electronic contour maps of the electron density and its Laplacian were calculated.
3. Results 
According to the obtained results, Figures 1 and 2, of the UV-ViS spectroscopy technique andviscometry indicated hyperchromism and hypochromism effect. Furthermore, the experimental results were depended on the concentration of the drug and affected the type of binding of Tamoxifen to DNA. Besides, the entangling of the whole binding sites of DNA was due to the hydrophobic and electrostatic interactions [11, 12]. 
Additionally, analyzing computational studies on the drug tamoxifen suggested that the mechanism of the local charge/energy distribution in the molecular system of tamoxifen plays an essential role in how this drug binds to DNA, Figure 3. 4. Discussion and Conclusion
 Based on the experimental results of the UV-ViS technique and viscometry, as well as the electronic/vibrational properties of the tamoxifen molecular system, it was defined that the Tamoxifencan place betweenthe base pairs, major and minor grooves; it also interacts with a back bone of DNA by electrostatic interactions. Therefore, all the DNA binding sites are entangled with Tamoxifen by the hydrophobic and electrostatic interactions. The internal diagram presents the absorbance of the tamoxifen in the presence of a different concentration of DNA at a wavelength of 250 nm.

Ethical Considerations
Compliance with ethical guidelines
This article is a meta-analysis with animal sample.

Funding
The paper was extracted from the MSc. thesis of the first author at the Department of Chemistry, School of Science, University of Qom, Qom.

Authors' contributions
Subject design: Reza Safari, Maryam Nejat Dehkordi; Experiments and calculations: Fatemeh Sharafi Bajgan; Analysis of results: Reza Safari, Maryam Nejat Dehkordi, Fatemeh Sharafi Bajgan; Text writing and review: All authors.

Conflicts of interest
The authors declared no conflict of interest.

Acknowledgements
We would like to express our gratitude to the research assistants and managers of the esteemed departments of Chemistry in Qom and Islamic Azad University (Shahrekord Branch) for providing the necessary research facilities and equipment.


References

1. Shokohi-Pour Z, Chiniforoshan H, Sabzalian MR, Esmaeili SA, Momtazi-Borojeni AA. Cobalt (II) complex with novel unsymmetrical tetradentate Schiff base (ON) ligand: In vitro cytotoxicity studies of complex, interaction with DNA/protein, molecular docking studies, and antibacterial activity. J Biomol Struct Dyn. 2018; 36(2):532-49. [DOI:10.1080/07391102.2017.1287006] [PMID]
2. Agudelo D, Bourassa P, Bérubé G, Tajmir-Riahi HA. Review on the binding of anticancer drug doxorubicin with DNA and tRNA: Structural models and antitumor activity. J Photochem Photobiol B. 2016; 158:274-9. [DOI:10.1016/j.jphotobiol.2016.02.032] [PMID]
3. Liu W, Guo Y, Wang K, Zhou X, Wang Y, Lü J, et al. Atomic force microscopy-based single-molecule force spectroscopy detects DNA base mismatches. Nanoscale. 2019; 11(37):17206-10. [DOI:10.1039/C9NR05234H] [PMID]
4. Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018; 186:1-24. [DOI:10.1016/j.pharmthera.2017.12.012] [PMID]
5. Gong L, Tang H, Luo Z, Sun X, Tan X, Xie L, et al. Tamoxifen induces fatty liver disease in breast cancer through the MAPK8/FoxO pathway. Clin Transl Med. 2020; 10(1):137-50. [DOI:10.1002/ctm2.5] [PMID] [PMCID]
6. Shagufta, Ahmad I. Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives. Eur J Med Chem. 2018; 143:515-31. [DOI:10.1016/j.ejmech.2017.11.056] [PMID]
7. Di Benedetto L, Giovanale V, Caserta D. Endometrial tubal metaplasia in a young puerperal woman after breast cancer. Int J Clin Exp Pathol. 2015; 8(6):7610-3. [PMCID]
8. Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American society of clinical oncology clinical practice guideline focused update. J Clin Oncol. 2014; 32(21):2255-69. [DOI:10.1200/JCO.2013.54.2258] [PMID] [PMCID]
9. Hassan AA, Aly AA, Mohamed NK, El Shaieb KM, Makhlouf MM, Abdelhafez EMN, et al. Design, synthesis, and DNA interaction studies of furo-imidazo [3.3.3] propellane derivatives: Potential anticancer agents. Bioorg Chem. 2019; 85:585-99. [DOI:10.1016/j.bioorg.2019.02.027] [PMID] [PMCID]
10. Dareini M, Amiri Tehranizadeh Z, Marjani N, Taheri R, Aslani-Firoozabadi S, Talebi A, et al. A novel view of the separate and simultaneous binding effects of docetaxel and anastrozole with calf thymus DNA: Experimental and in silico approaches. Spectrochim Acta A Mol Biomol Spectrosc. 2020; 228:117528. [DOI:10.1016/j.saa.2019.117528] [PMID]
11. Nejat Dehkordi M, Akerman B. Interaction of DNA with water soluble complex of Nickle and formation of DNA cross-links. Chem Biol Interact. 2018; 282:55-62. [DOI:10.1016/j.cbi.2018.01.007] [PMID]
12. Tan LF, Liu XH, Chao H, Ji LN. Synthesis, DNA-binding and photocleavage studies of ruthenium (II) complex with 2-(3′-phenoxyphenyl) imidazo [4, 5-f] [1, 10] phenanthroline. J Inorg Biochem. 2007; 101(1):56-63. [DOI:10.1016/j.jinorgbio.2006.08.006] [PMID]
13. Brodzki A, Tatara MR, Brodzki P, Balicki I. DNA adduct assessment during antihormonal treatment of perianal gland tumors with tamoxifen in male dogs. In Vivo. 2019; 33(3):731-5. [DOI:10.21873/invivo.11532] [PMID] [PMCID]
14. Rajaniemi H, Koskinen M, Mäntylä E, Hemminki K. DNA binding of tamoxifen and its analogues: Identification of the tamoxifen-DNA adducts in rat liver. Toxicol Lett. 1998; 102-3:453-7. [DOI:10.1016/S0378-4274(98)00338-5]
15. Matta CF, Boyd RJ. The quantum theory of atoms in molecules: From solid state to DNA and drug design. Germany: Wiley; 2007. [DOI:10.1002/9783527610709]
16. Shameera Ahamed TK, Rajan VK, Sabira K, Muraleedharan K. DFT and QTAIM based investigation on the structure and antioxidant behavior of lichen substances Atranorin, Evernic acid and Diffractaic acid. Comput Biol Chem. 2019; 80:66-78. [DOI:10.1016/j.compbiolchem.2019.03.009] [PMID]
17. Dehkordi MN, Bordbar AK, Mehrgardi MA, Mirkhani V. Spectrophotometric study on the binding of two water soluble Schiff base complexes of Mn (III) with ct-DNA. J Fluoresc. 2011; 21(4):1649-58. [DOI:10.1007/s10895-011-0854-y] [PMID]
18. Zhao Z, Li E, Qin Y, Liu X, Zou Y, Wu H, et al. Density functional theory (DFT) studies of vanadium-titanium based selective catalytic reduction (SCR) catalysts. J Environ Sci (China). 2020; 90:119-37. [DOI:10.1016/j.jes.2019.11.008] [PMID]
19. Rojas S, Parravicini O, Vettorazzi M, Tosso R, Garro A, Gutiérrez L, et al. Combined MD/QTAIM techniques to evaluate ligand-receptor interactions. Scope and limitations. Eur J Med Chem. 2020; 208:112792. [DOI:10.1016/j.ejmech.2020.112792] [PMID]
20. Matta CF. Modeling biophysical and biological properties from the characteristics of the molecular electron density, electron localization and delocalization matrices, and the electrostatic potential. J Comput Chem. 2014; 35(16):1165-98. [DOI:10.1002/jcc.23608]
21. Hammoudan I, Chtita S, Riffi-Temsamani D. QTAIM and IRC studies for the evaluation of activation energy on the C=P, C=N and C=O Diels-Alder reaction. Heliyon. 2020; 6(8):e04655. [DOI:10.1016/j.heliyon.2020.e04655] [PMID] [PMCID]
22. Levine IN. Quantum chemistry. London: Person; 2013.
23. Biegler F, Schonbohm H, Bader RWF. AIM2000 Program Package, Ver. 2.0. Canada, Hamilton: McMaster University; 2002.
24. von Rudorff GF, von Lilienfeld OA. Atoms in molecules from alchemical perturbation density functional theory. J Phys Chem B. 2019; 123(47):10073-82. [DOI:10.1021/acs.jpcb.9b07799] [PMID]
25. Shahbazy M, Pakravan P, Kompany-Zareh M. Multivariate spectrochemical analysis of interactions of three common Isatin derivatives to calf thymus DNA in vitro. J Biomol Struct Dyn. 2017; 35(12):2539-56. [DOI:10.1080/07391102.2016.1225604] [PMID]
26. Soni A, Khurana P, Singh T, Jayaram B. A DNA intercalation methodology for an efficient prediction of ligand binding pose and energetics. Bioinformatics. 2017; 33(10):1488-96. [DOI:10.1093/bioinformatics/btx006] [PMID]
27. Cui F, Liu Q, Luo H, Zhang G. Spectroscopic, viscositic and molecular modeling studies on the interaction of 3’-azido-daunorubicin thiosemicarbazone with DNA. J Fluoresc. 2014; 24(1):189-95. [DOI:10.1007/s10895-013-1285-8] [PMID] [PMCID]
28. Shahabadi N, Mohammadi S, Alizadeh R. DNA interaction studies of a new platinum(II) complex containing different aromatic dinitrogen ligands. Bioinorg Chem Appl. 2011; 2011:429241. [DOI:10.1155/2011/429241] [PMID] [PMCID]
29. Krokidis MG, Molphy Z, Efthimiadou EK, Kokoli M, Argyri SM, Dousi I, et al. Assessment of DNA topoisomerase I unwinding activity, radical scavenging capacity, and inhibition of breast cancer cell viability of N-alkyl-acridones and N,N’-dialkyl-9,9’-biacridylidenes. Biomolecules. 2019; 9(5):177. [DOI:10.3390/biom9050177] [PMID] [PMCID]
30. Qais FA, Ahmad I. In vitro interaction of cefotaxime with calf thymus DNA: Insights from spectroscopic, calorimetric and molecular modelling studies. J Pharm Biomed Anal. 2018; 149:193-205. [DOI:10.1016/j.jpba.2017.10.016] [PMID]
31. Rahman Y, Afrin S, Husain MA, Sarwar T, Ali A, Shamsuzzaman, et al. Unravelling the interaction of pirenzepine, a gastrointestinal disorder drug, with calf thymus DNA: An in vitro and molecular modelling study. Arch Biochem Biophys. 2017; 625-6:1-12. [DOI:10.1016/j.abb.2017.05.014] [PMID]
32. Nogueira JJ, Plasser F, González L. Electronic delocalization, charge transfer and hypochromism in the UV absorption spectrum of polyadenine unravelled by multiscale computations and quantitative wavefunction analysis. Chem Sci. 2017; 8(8):5682-91. [DOI:10.1039/C7SC01600J] [PMID] [PMCID]
33. Das RP, Singh BG, Kunwar A, Ramani MV, Subbaraju GV, Hassan PA, et al. Tuning the binding, release and cytotoxicity of hydrophobic drug by Bovine Serum Albumin nanoparticles: Influence of particle size. Colloids Surf B Biointerfaces. 2017; 158:682-8. [DOI:10.1016/j.colsurfb.2017.07.048] [PMID]
34. Shahabadi N, Hakimi M, Morovati T, Fatahi N. DNA binding affinity of a macrocyclic copper (II) complex: Spectroscopic and molecular docking studies. Nucleosides Nucleotides Nucleic Acids. 2017; 36(8):497-510. [DOI:10.1080/15257770.2017.1332370] [PMID]
35. Shahabadi N, Akhtarshenas S, Hadidi S. Synthesis, characterization and DNA interaction studies of new copper complex containing pseudoephedrine hydrochloride drug. Nucleosides Nucleotides Nucleic Acids. 2019; 38(9):680-99. [DOI:10.1080/15257770.2019.1599909] [PMID]
36. Karimi Moghadam S, Dorostkar R, Hesami Takallou S. [Evaluation of human endogenous retrovirus K expression in the blood of breast cancer patients (Persian)]. J Arak Univ Med Sci. 2018; 20(11):87-95. https://www.sid.ir/FileServer/JF/651139612809
37. Yousefi Z, F Homayie, S Rafei. [The evaluation of the endometrial thickness of amenorrhea breast cancer patients treated with tamoxifen (Persian)]. J Arak Univ Med Sci. 2011; 14(5):101-7.‏ https://www.sid.ir/en/journal/ViewPaper.aspx?id=215602
38. Anoushirvani AA, Ahmadi A, Aghabozorgi R, Khalili S, Sahraei M, Fereydouni T, et al. [Gengenotypic evaluation of Hsa-miR-433-3p binding site in the regulatory region of TYMS in breast cancer patients (Persian)]. J Arak Univ Med Sci. 2018; 21(2):1-9. ‏ http://jams.arakmu.ac.ir/article-1-5608-en.pdf