An In Vitro Study of Aromatic Stacking of Drug Molecules

  • Shelley N. Jackson
  • Damon C. Barbacci
  • Antonello Bonci
  • Amina S. WoodsEmail author
Research Article


In this paper, drug–drug chemical interactions between two different aromatic compounds were studied by mass spectrometry. Specifically, we examined non-covalent complexes (NCX) between paclitaxel, a chemotherapeutic compound, and medications widely used in palliative care for depression, psychosis, and anxiety. It is unknown whether psychotropic medications directly interact with paclitaxel. Here, we use a simple and rapid electrospray ionization mass spectrometry in vitro assay, which has been predictive in the case of neuropeptides, to measure the relative strength of non-covalent interactions. This chemical interaction is most likely due to the overlap of aromatic rings of π-orbitals between paclitaxel and five commonly used medications: diazepam, clonozepam, sertraline, fluoxetine, and haloperidol. Molecular modeling illustrates that differences in the stability of the NCXs are likely due to the distance between the aromatic rings present in both the paclitaxel and antidepressant medications.

Graphical Abstract


Non-covalent interactions Drug–drug interactions π-Stacking 



The authors acknowledge Dr. Lorenzo Leggio, Dr. Michelle Leff, Dr. Gail Seabold, and Dr. J. Albert Schultz for their comments and Dr. Martha Vestling for her critical insight. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. The authors declare that they have no competing interests.


  1. 1.
    Peterson, J.F., Bates, D.W.: Preventable medication errors: identifying and eliminating serious drug interactions. J. Am. Pharm. Assoc. 41, 159–160 (2001)Google Scholar
  2. 2.
    Scott, A., Scott, G.N.: Mechanisms of drug interactions. Pharm. Tech Topics. 18, 1–24 (2013)Google Scholar
  3. 3.
    Roberts, A.G., Gibbs, M.E.: Mechanisms and the clinical relevance of complex drug-drug-drug interactions. Clin. Pharmacol. 10, 123–134 (2018)Google Scholar
  4. 4.
    Loo, J.A.: Electrospray ionization mass spectrometry: a technology for studying noncovalent macromolecular complexes. Int. J. Mass Spectrom. 200, 175–186 (2000)CrossRefGoogle Scholar
  5. 5.
    Schug, K.A., Linder, W.: Noncovalent binding between guanidinium and anionic groups: focus on biological- and synthetic-based arginine/guanidinium interactions with phosph[on]ate and sulf[on]ate residues. Chem. Rev. 105, 67–114 (2005)CrossRefGoogle Scholar
  6. 6.
    Strittmatter, E.F., Schnier, P.D., Klassen, J.S., Williams, E.R.: Dissociation energies of deoxyribose nucleotide dimer anions measured using blackbody infrared radiative dissociation. J. Am. Soc. Mass Spectrom. 10, 1095–1104 (1999)CrossRefGoogle Scholar
  7. 7.
    Xu, Y., Afonso, C., Gimbert, Y., Fournier, F., Dong, X., Wen, R., Tabet, J.-C.: Gas phase self-association of eudistomin u controlled bu gas phase acidity and origin of its interaction with nucleobases. Int. J. Mass Spectrom. 286, 43–52 (2009)CrossRefGoogle Scholar
  8. 8.
    Hofstadler, S.A., Sannes-Lowery, K.A.: Applications of ESI-MS in drug discovery: interrogation of noncovalent complexes. Nat. Rev. Drug Discov. 5, 585–595 (2006)CrossRefGoogle Scholar
  9. 9.
    Hofstadler, S.A., Griffey, R.H.: Analysis of noncovalent complexes of DNA and RNA by mass spectrometry. Chem. Rev. 101, 377–390 (2001)CrossRefGoogle Scholar
  10. 10.
    Rosu, F., Pirotte, S., De Pauww, E., Gabelica, V.: Positive and negative ion mode ESI-MS and MS/MS for studying drug-DNA complexes. Int. J. Mass Spectrom. 253, 156–171 (2006)CrossRefGoogle Scholar
  11. 11.
    Gupta, R., Beck, J.L., Ralph, S.F., Sheil, M.M., Aldrich-Wright, J.R.: Comparison of the binding stoichiometries of positively charged DNA-binding drugs using positive and negative ion electrospray ionization mass spectrometry. J. Am. Soc. Mass Spectrom. 15, 1382–1391 (2004)CrossRefGoogle Scholar
  12. 12.
    Wan, C., Cui, M., Song, F., Liu, Z., Liu, S.: A study of the non-covalent interaction between flavonoids and DNA triplexes by electrospray ionization mass spectrometry. Int. J. Mass Spectrom. 283, 48–55 (2009)CrossRefGoogle Scholar
  13. 13.
    Pashynska, V.A., Van den Heuvel, H., Claeys, M., Kosevich, M.V.: Characterization of noncovalent complexes of antimalarial agents of the artemisin-type and FE(III)-heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry. J. Am. Soc. Mass Spectrom. 15, 1181–1190 (2004)CrossRefGoogle Scholar
  14. 14.
    Barbacci, D., Jackson, S.N., Muller, L., Egan, T., Lewis, E.K., Schultz, J.A., Woods, A.S.: Cellular membrane phospholipids act as a depository for quaternary amine containing drugs thus competing with the acetylcholine/nicotinic receptor. J. Proteome Res. 11, 3382–3389 (2012)CrossRefGoogle Scholar
  15. 15.
    Spiegel, D.: Cancer and depression. Br. J. Psychiatry. 168, 109–116 (1996)CrossRefGoogle Scholar
  16. 16.
    Spiegel, D., Giese-Davis, J.: Depression and cancer: mechanisms and disease progression. Biol. Psychiatry. 54, 269–282 (2003)CrossRefGoogle Scholar
  17. 17.
    Bernard, S.A., Bruera, A.: Drug interactions in palliative care. J. Clin. Oncol. 18, 1780–1799 (2000)CrossRefGoogle Scholar
  18. 18.
    Wall, M.E., Wani, M.C.: Camptothecin and taxol: discovery to clinic-thirteenth Bruce F. Cain Memorial Award Lecture. Cancer Res. 55, 753–760 (1995)Google Scholar
  19. 19.
    Wani, M.C., Taylor, H.L., Wall, M.E., Coggon, P., McPhail, A.T.: Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 93, 2325–2327 (1971)CrossRefGoogle Scholar
  20. 20.
    McGuire, W.P., Rowinsky, E.K., Rosenshein, N.B., Grumbine, F.C., Ettinger, D.S., Armstrong, D.K., Donehower, R.C.: Taxol a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann. Intern. Med. 111, 273–279 (1989)CrossRefGoogle Scholar
  21. 21.
    Klauber, N., Parangi, S., Flynn, E., Hamel, E., D'Amato, R.J.: Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res. 57, 81–86 (1997)Google Scholar
  22. 22.
    Mani, S., McDaid, H., Hamilton, A., Hochster, H., Cohen, M.B., Khabelle, D., Griffin, T., Lebwohl, D.E., Liebes, L., Muggia, F., Horwitz, S.B.: Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin. Cancer Res. 10, 1289–1298 (2004)CrossRefGoogle Scholar
  23. 23.
    Matreja, P.S., Badyal, D.K., Khosla, P., Deswal, R.S.: Effectiveness and acceptability of sertraline and citalopram in major depressive disorder: pragmatic randomized open-label comparison. Hum Psychopharmacol. 22, 477–482 (2007)CrossRefGoogle Scholar
  24. 24.
    Griffin III, C.E., Kaye, A.M., Bueno, F.R., Kaye, A.D.: Benzodiazepine pharmacology, and central nervous system–mediated effects. Ochsner J. 13, 214–223 (2013)Google Scholar
  25. 25.
    Santos, E., Cardoso, D., Neves, H., Cunha, M., Rodrigues, M., Apóstolo, J.: Effectiveness of haloperidol prophylaxis in critically ill patients with a high risk of delirium: a systematic review. JBISRIR. 15, 1440–1472 (2017)Google Scholar
  26. 26.
    Haque, R., Shi, J., Schottinger, J.E., Ahmed, S.A., Cheetham, T.C., Chung, J., Avila, C., Kleinman, K., Habel, L.A., Fletcher, S.W., Kwan, M.L.: Tamoxifen and antidepressant drug interaction among a cohort of 16 887 breast cancer survivors. J. Natl. Cancer Inst. 108, 1–8 (2016)CrossRefGoogle Scholar
  27. 27.
    Sinnokrot, M.O., Valeev, E.F., Sherrill, C.D.: Estimates of the ab initio limit for pi-pi interactions: the benzene dimer. J. Am. Chem. Soc. 124, 10887–10893 (2002)CrossRefGoogle Scholar
  28. 28.
    McGaughey, G.B., Gagné, M., Rappé, A.K.: Pi-Stacking interactions. Alive and well in proteins. J. Biol. Chem. 273, 15458–15463 (1998)CrossRefGoogle Scholar
  29. 29.
    Sherman, C.L., Brodbelt, J.S., Marchand, A.P., Poola, B.: Electrospray ionization mass spectrometric detection of self-assembly of a crown ether complex directed by π-stacking interactions. J. Am. Soc. Mass Spectrom. 16, 1162–1171 (2005)CrossRefGoogle Scholar
  30. 30.
    Franski, R., Gierczyk, B.: ESI-MS detection of very weak π-stacking interactions in the mixed-ligand sandwich complexes formed by substituted benzo-crown ethers and metal cations. J. Am. Soc. Mass Spectrom. 21, 545–549 (2010)CrossRefGoogle Scholar
  31. 31.
    Tan, W., Zhou, J., Yuan, G.: Electrospray ionization mass spectrometry probing of binding affinity of berbamine, a flexible cyclic alkaloid from traditional Chinese medicine, with G-quadruplex DNA. Rapid Commun. Mass Spectrom. 28, 143–147 (2014)CrossRefGoogle Scholar
  32. 32.
    Troc, A., Gajewy, J., Danikiewicz, W., Kwit, M.: Specific noncovalent association of chiral large-ring hexaimines: ion mobility mass spectrometry and PM7 study. Chem. Eur. J. 22, 13258–13264 (2016)CrossRefGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  • Shelley N. Jackson
    • 1
  • Damon C. Barbacci
    • 2
  • Antonello Bonci
    • 3
  • Amina S. Woods
    • 1
    • 4
    Email author
  1. 1.Structural Biology Unit, Integrative Neuroscience BranchNIDA IRP, NIHBaltimoreUSA
  2. 2.Ionwerks Inc.HoustonUSA
  3. 3.Office of the DirectorNIDA IRP, NIHBaltimoreUSA
  4. 4.Structural Biology Unit, Cellular Neurobiology BranchNIDA IRP, NIHBaltimoreUSA

Personalised recommendations