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Investigation of interactions of doxorubicin with purine nucleobases by molecular modeling

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Abstract

Doxorubicin, an anthracycline antibiotic with anti-tumor activity, is produced by the bacterium Streptomyces peucetius. The interactions between doxorubicin and genetic material and the details of the intercalation with DNA have been controversial issues. Thus, the interactions of doxorubicin with purine nucleobases were studied by quantum mechanical methods. Initially, conformer analyses of doxorubicin were performed with Spartan 08 software and 319 different conformers from 422 initial structures for doxorubicin were obtained. Geometry optimizations and frequency analyses were performed for each structure using density functional theory (DFT) at B3LYP/6-31G** level using Gaussian 09 software. The most stable 20 conformers of doxorubicin and tautomers of purine nucleobases were optimized again with ɷB97XD/6-31G** level and their interactions were also analyzed at the same level. The Discovery Studio 3.5 Visualizer was used to draw the initial and optimized structures of investigated geometries. The noncovalent interactions (NCIs) were visualized by calculating reduced density gradient (RDG) with Multiwfn program. The color-filled isosurfaces and RDG scatter maps of most stable interaction geometries were plotted by Visual Molecular Dynamics (VMD) software and Gnuplot 5.3 software, respectively. This study showed that adenine, guanine, and hypoxanthine nucleobases interact with doxorubicin by forming strong hydrogen bonds and π-π interactions. Considering the normal cellular conditions, the effect of solvent (water) on the interaction geometries were also analyzed and when compared to gas phase it was determined that the movements of the molecules were restricted and there was a minimal change between initial and optimized structures in the aqueous phase.

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References

  1. Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT (1946) Nitrogen mustard therapy: use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia, and certain allied and miscellaneous disorders. JAMA 105:475–476. https://doi.org/10.1001/jama.1946.02870380008004

    Article  Google Scholar 

  2. DeVita VT, Rosenberg SA (2012) Two hundred years of cancer research. NEJM 366:2207–2214. https://doi.org/10.1056/NEJMra1204479

    Article  CAS  PubMed  Google Scholar 

  3. Farber S, Diamond LK, Mercer RD, Sylvester RJ, Wolff JA (1948) Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). NEJM 238:787–794. https://doi.org/10.1056/NEJM194806032382301

    Article  CAS  PubMed  Google Scholar 

  4. Arcamone F, Cassineffi G, Di Marco A, Gaetani M (1967) Patent application Farmitalia Research Laboratories 251 NSA.

  5. Bonadonna G, Monfardinit S, De Lena M, Fossati-Bellani F (1969) Clinical evaluation of adriamycin, a new antitumour antibiotic. Br Med J 3:503–506. https://doi.org/10.1136/bmj.3.5669.503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ma P, Mumper RJ (2013) Anthracycline Nano-delivery systems to overcome multiple drug resistance: a comprehensive review. Nano Today 8:313–331. https://doi.org/10.1016/j.nantod.2013.04.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229. https://doi.org/10.1124/pr.56.2.6

    Article  CAS  PubMed  Google Scholar 

  8. Agudelo D, Bourassa P, Bérubé G, Tajmir-Riahi HA (2016) Review on the binding of anticancer drug doxorubicin with DNA and tRNA: structural models and antitumor activity. J Photochem Photobiol B 158:274–279. https://doi.org/10.1016/j.jphotobiol.2016.02.032

    Article  CAS  PubMed  Google Scholar 

  9. Goto S, Ihara Y, Urata Y, Izumi S, Abe K, Koji T, Kondo T (2001) Doxorubicin-induced DNA intercalation and scavenging by nuclear glutathione S-transferase π. FASEB J 15:2702–2713. https://doi.org/10.1096/fj.01-0376com

    Article  CAS  PubMed  Google Scholar 

  10. Yao F, Duan J, Wang Y, Zhang Y, Guo Y, Guo H, Kang X (2015) Nanopore single-molecule analysis of DNA–doxorubicin interactions. Anal Chem 87:338–342. https://doi.org/10.1021/ac503926g

    Article  CAS  PubMed  Google Scholar 

  11. Agudelo D, Bourassa P, Bérubé G, Tajmir-Riahi HA (2014) Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: structural features and biological implications. Int J Biol Macromol 66:144–150. https://doi.org/10.1016/j.ijbiomac.2014.02.028

    Article  CAS  PubMed  Google Scholar 

  12. Gewirtz D (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741. https://doi.org/10.1016/s0006-2952(98)00307-4

    Article  CAS  PubMed  Google Scholar 

  13. Sinha BK, Mimnaugh EG (1990) Free radicals and anticancer drug resistance: oxygen free radicals in the mechanisms of drug cytotoxicity and resistance by certain tumors. Free Radic Biol Med 8:567–581. https://doi.org/10.1016/0891-5849(90)90155-C

    Article  CAS  PubMed  Google Scholar 

  14. Bolhuis A, Aldrich-Wright JR (2014) DNA as a target for antimicrobials. Bioorg Chem 55:51–59. https://doi.org/10.1016/j.bioorg.2014.03.009

    Article  CAS  PubMed  Google Scholar 

  15. Airoldi M, Barone G, Gennaro G, Giuliani AM, Giustini M, Hager MH (2014) Interaction of doxorubicin with polynucleotides A spectroscopic study. Biochemistry 53:2197–2207. https://doi.org/10.1021/bi401687v

    Article  CAS  PubMed  Google Scholar 

  16. Neidle S, Abraham Z (1984) Structural and sequencedependent aspects of drug intercalation into nucleic acids. Crit Rev Biochem Mol Biol 17:73–121. https://doi.org/10.3109/10409238409110270

    Article  CAS  Google Scholar 

  17. The History of Cancer. American Cancer Society http://www.cancer.org/cancer/cancerbasics/thehistoryofcancer. Accessed 29 March 2020

  18. Bonadonna G, Monfardini S, De Lena M, Fossati-Bellani F, Beretta G (1970) Phase I and preliminary phase II evaluation of adriamycin (NSC 123127). Cancer Res 30:2572–2582

    CAS  PubMed  Google Scholar 

  19. Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev 34:106–135. https://doi.org/10.1002/med.21280

    Article  CAS  PubMed  Google Scholar 

  20. Zhu S, Yan L, Ji X, Lu W (2010) Conformational diversity of anthracycline anticancer antibiotics: a density functional theory calculation. J Mol Struc-THEOCHEM 951:60–68. https://doi.org/10.1016/j.theochem.2010.04.008

    Article  CAS  Google Scholar 

  21. Chaires JB, Dattagupta ND, Crothers DM (1983) Binding of daunomycin to calf thymus nucleosomes. Biochemistry 22:284–292. https://doi.org/10.1021/bi00271a009

    Article  CAS  PubMed  Google Scholar 

  22. Yang F, Tevesa SS, Kempb CJ, Henikoffa S (2014) Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta 1845:84–89. https://doi.org/10.1016/j.bbcan.2013.12.002

    Article  CAS  PubMed  Google Scholar 

  23. Aubel-Sadron G, Londos-Gagliardi D (1984) Daunorubicin and doxorubicin, anthracycline antibiotics, a physicochemical and biological review. Biochimie 66:333–352. https://doi.org/10.1016/0300-9084(84)90018-X

    Article  CAS  PubMed  Google Scholar 

  24. Perez-Arnaiz C, Busto N, Leal JM, García B (2014) New insights into the mechanism of the DNA/doxorubicin interaction. J Phys Chem B 118:1288–1295. https://doi.org/10.1021/jp411429g

    Article  CAS  PubMed  Google Scholar 

  25. Spartan 08 (2008) Wavefunction Inc., Irvine, CA. https://www.wavefun.com/. Accessed 29 March 2020

  26. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision E.01, Gaussian, Inc., Wallingford CT.

  27. Minenkov Y, Singstad A, Occhipinti G, Jensen VR (2012) The accuracy of DFT-optimized geometries of functional transition metal compounds: a validation study of catalysts for olefin metathesis and other reactions in the homogeneous phase. Dalton Trans 41:5526–5541. https://doi.org/10.1039/c2dt12232d

    Article  CAS  PubMed  Google Scholar 

  28. Accelrys Software Inc., Discovery Studio 3.5, San Diego, CA, USA, 2012.

  29. Johnson ER, Keinan S, Mori-Sanchez P, Contreras-Garcia J, Cohen AJ, Yang W (2010) Revealing noncovalent interactions. J Am Chem Soc 132:6498–6506. https://doi.org/10.1021/ja100936w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33:580–592. https://doi.org/10.1002/jcc.22885

    Article  CAS  PubMed  Google Scholar 

  31. Humphrey W, Dalke A, Schulten K (1996) VMD: Visual Molecular Dynamics. J Mol Graph 14:33–38. https://doi.org/10.1016/0263-7855(96)00018-5

    Article  CAS  PubMed  Google Scholar 

  32. Williams T, Kelley C (2011) Gnuplot 5.3 patchlevel 0: an interactive plotting program. http://gnuplot.info. Accessed 29 March 2020

  33. Singh V, Fedeles BI, Essigmann JM (2015) Role of tautomerism in RNA biochemistry. RNA 21:1–13. https://doi.org/10.1261/rna.048371.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Colominas C, Luque FJ, Orozco M (1996) Tautomerism and protonation of guanine and cytosine. Implications in the formation of hydrogen-bonded complexes. J Am Chem Soc 118:6811–6821. https://doi.org/10.1021/ja954293l

    Article  CAS  Google Scholar 

  35. Singh RK, Ortiz JV, Mishra MK (2010) Tautomeric forms of adenine: vertical ionization energies and dyson orbitals. Int J Quantum Chem 110:1901–1915. https://doi.org/10.1002/qua.22363

    Article  CAS  Google Scholar 

  36. Guerra CF, Bickelhaupt FM, Saha S, Wang F (2006) Adenine tautomers: relative stabilities, ionization energies, and mismatch with cytosine. J Phys Chem A 110:4012–4020. https://doi.org/10.1021/jp057275r

    Article  CAS  Google Scholar 

  37. Hanus M, Kabelac M, Rejnek J, Ryjacek F, Hobza P (2004) Correlated ab initio study of nucleic acid bases and their tautomers in the gas phase, in a microhydrated environment, and in aqueous solution. Part 3 Adenine. J Phys Chem B 108:2087–2097. https://doi.org/10.1021/jp036090m

    Article  CAS  Google Scholar 

  38. Hanus M, Ryjácek F, Kabelác M, Kubar T, Bogdan TV, Trygubenko SA, Hobza P (2003) Correlated ab initio study of nucleic acid bases and their tautomers in the gas phase, in a microhydrated environment and in aqueous solution. guanine: surprising stabilization of rare tautomers in aqueous solution. J Am Chem Soc 125:7678–7688. https://doi.org/10.1021/ja034245y

    Article  CAS  PubMed  Google Scholar 

  39. Shukla MK, Leszczynski J (2005) Excited state proton transfer in guanine in the gas phase and in water solution: a theoretical study. J Phys Chem A 109:7775–7780. https://doi.org/10.1021/jp052340i

    Article  CAS  PubMed  Google Scholar 

  40. Costas ME, Acevedo-Chávez R (2012) Density functional theory study of hypoxanthine tautomerism in both the isolated state and a modeled-ideal aqueous solution at several heterocyclic protonation levels. J Solution Chem 41:864–878. https://doi.org/10.1007/s10953-012-9834-3

    Article  CAS  Google Scholar 

  41. Shukla MK, Leszczynski J (2000) A DFT investigation on effects of hydration on the tautomeric equilibria of hypoxanthine. J Mol Struc-THEOCHEM 529:99–112. https://doi.org/10.1016/S0166-1280(00)00536-4

    Article  CAS  Google Scholar 

  42. Snyder RD, Holt PA, Maguire JM, Trent JO (2013) Prediction of noncovalent Drug/DNA interaction using computational docking models: studies with over 1350 launched drugs. Environ Mol Mutagen 54:668–681. https://doi.org/10.1002/em.21796

    Article  CAS  PubMed  Google Scholar 

  43. Miroshnychenko KV, Shestopalova AV (2010) The effect of Drug-DNA interactions on the intercalation site formation. Int J Quantum Chem 110:161–176. https://doi.org/10.1002/qua.22290

    Article  CAS  Google Scholar 

  44. Graves DE, Velea LM (2000) Intercalative binding of small molecules to nucleic acids. Curr Org Chem 4:915–929. https://doi.org/10.2174/1385272003375978

    Article  CAS  Google Scholar 

  45. Lee CJ, Kang JS, Kim MS, Lee KP, Lee MS (2004) The study of doxorubicin and its complex with DNA by SERS and UV-resonance Raman spectroscopy. B Korean Chem Soc 25:1211. https://doi.org/10.5012/bkcs.2004.25.8.1211

    Article  CAS  Google Scholar 

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Acknowledgements

Some of the calculations were performed on TÜBİTAK (The Scientific and Technological Research Council of Turkey) TRUBA (Turkish National Science e-Infrastructure) resources.

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  1. Esra Şahin Akdeniz

    Present address: İzmir Institute of Technology, Faculty of Science, Department of Molecular Biology and Genetics, Urla, 35430, İzmir, Turkey

Authors and Affiliations

  1. Ege University, Graduate School of Natural and Applied Sciences, Biochemistry Programme, Bornova, 35100, İzmir, Turkey

    Esra Şahin Akdeniz & Cenk Selçuki

  2. Ege University, Faculty of Science, Department of Biochemistry, Bornova, 35100, İzmir, Turkey

    Cenk Selçuki

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  1. Esra Şahin Akdeniz
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  2. Cenk Selçuki
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All authors contributed to study conception and design. Material preparation, data collection, and analysis were performed by Esra Sahin Akdeniz. The first draft of the manuscript was written by Esra Sahin Akdeniz and Cenk Selcuki commented on previous versions of the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Esra Şahin Akdeniz.

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Şahin Akdeniz, E., Selçuki, C. Investigation of interactions of doxorubicin with purine nucleobases by molecular modeling. J Mol Model 28, 69 (2022). https://doi.org/10.1007/s00894-022-05031-z

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