Theoretical insights into the intermolecular and mechanisms of covalent interaction of Flutamide drug with COOH and COCl functionalized carbon nanotubes: A DFT approach

Document Type : Research Article


1 Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, Iran

2 Department of Chemistry, University of Birjand, Birjand, Iran

3 Department of chemical engineering, Ferdowsi University of Mashhad, Mashhad, Iran


In this study, it is attempted to scrutinize the noncovalent interaction and two mechanisms of covalent between Flutamide anti-cancer drug (FLU) and functionalized carbon nanotubes (f-CNT) employing density functional theory (DFT) calculations regarding their geometries, binding energies and topological features of the electron density in the water solution. For designed noncovalent interactions, binding energies, natural bond orbital (NBO), atom in molecule (AIM) and quantum molecular descriptors analyses were applied for further understanding of the adsorption process. The computed theoretical results confirmed that binding of Flutamide molecule with functionalized CNT is thermodynamically suitable and among two considered systems containing COOH functionalized CNT (NTCOOH) and COCl functionalized CNT (NTCOCl), the NTCOOH revealed more binding energy value which suggests it as a favorable system as a drug delivery within biological and chemical systems (noncovalent). NTCOOH and NTCOCl can bond to the NH group of flutamide through OH (COOH mechanism) and Cl (COCl mechanism) groups, respectively. Finally, to obtain the values of activation energies, the activation enthalpies and the activation Gibbs free energies of two considered pathways different calculations were performed and the results have been compared with each other. Numerical studies for calculating activation parameters related to the COOH mechanism show higher values than those related to the COCl mechanism and therefore COOH mechanism can be suitable for noncovalent functionalization. These results could be generalized to other similar drugs.

Graphical Abstract

Theoretical insights into the intermolecular and mechanisms of covalent interaction of Flutamide drug with COOH and COCl functionalized carbon nanotubes: A DFT approach


1] S. Iiima and T. Ichihashi, Single-shell carbon nanotubes of 1-nm diameter. Nature., 363 (1993) 603-605.
[2] V. Derycke, R. Martel, J. Appenzeller and Ph. Avouris, Controlling doping and carrier inection in carbon nanotube transistors Appl. Phys. Lett., 80 (2002) 2773-2775.
[3] P.M. Alderton and J. Gross, Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model. Cancer Res., 52 (1992) 194–201
[4] Z. Mahdavifar and R. Moridzadeh, Theoretical prediction of encapsulation and adsorption of platinum-anticancer drugs into single walled boron nitride and carbon nanotubes. Incl. Phenom. Macrocycl. Chem., 79 (2014) 443–457.
[5] R. Wang and D. Zhang, Theoretical Study of the Adsorption of Carbon Monoxide on Pristine and silicon-doped Boron Nitride
Nanotubes. Aust. Chem., 61 (2009) 941–945.
[6] D. Pantarotto, P. Briand, M. Prato and A. Bianco, Translocation of bioactive peptides across cell membranes by carbon nanotubes. Chem. Commun., 1 (2004) 16-17.
[7] B. Ttrzaskowski, A.F. albout and L. Adamowicz, Molecular dynamics studies of protein-fragment models encapsulated into carbon nanotubes. Chem. Phys. Lett., 430 (2006) 97-100.
[8] D. Pantarotto, C.D. Partidos and J. Hoebeke, Immunization with peptide-functionalized carbon nanotubes enhances virus-specific neutralizing antibody responses. Chem. Biol., 10 (2003) 961–966.
[9] R. Singh, D. Pantarotto and D. McCarthy, Binding and condensation of plasmid DNA onto functionalized carbon nanotubes: toward the construction of nanotubebased gene delivery vectors. Am. Chem. Soc., 127 (2005) 4388–4396.
[10] M. Prato, K. Kostarelos and A. Bianco, Functionalized carbon nanotubes in drug design and discovery. Acc. Chem. Res., 41 (2007) 60–68.
[11] A. Bianco, K. Kostarelos, C.D. Partidos and M. Prato, Biomedical applications of functionalized carbon nanotubes. Chem. Commun., 5 (2005) 571–577.
[12] A. Saberinasab, H. Raissi and H. Hashemzadeh, Understanding the Effect of Vitamin B6 and PEG Functionalization on Improving the Performance of Carbon Nanotubes in Temozolomide Anticancer Drug Transportation. J. Phys. D. Appl. Phys., 52 (2019).
[13] N. Saikia, R.C. Deka, Theoretical study on pyrazinamide adsorption onto covalently functionalized (5, 5) metallic single-walled carbon nanotube. Chem. Phys. Lett., 2010, 500, 65–70.
[14] H. Shaki, H. Raissi, F. Mollania and H. Hashemzadeh, Modeling the interaction between anti-cancer drug penicillamine and pristine and functionalized carbon nanotubes for medical applications: density functional theory investigation and a molecular dynamics simulation. J. Biomol. Struct. Dyn., (2019) 1–13
[15] N.W.S. Kam and H. Dai, Carbon nanotubes as intracellular protein transporters: generality and biological functionality. J. Am. Chem. Soc., 127 (2005) 6021–6026.
[16] M. Gallo, A. Favila and D.G. Mitnik, DFT studies of functionalized carbon nanotubes and fullerenes as nanovectors for drug delivery of antitubercular compounds. Chem. Phys. Lett., 447 (2007) 105–109.
[17] K. Aima, M. Yudasaka and T. Murakami, Carbon Nanohorns as Anticancer Drug Carriers. Mol. Pharm., 2 (2005) 475–480.
[18] H. Chegini, A. Morsali, M.R. Bozorgmehr and S.A. Beyramabadi, Theoretical study on the mechanism of covalent bonding of dapsone onto functionalised carbon nanotubes: effects of coupling agent. Prog. React. Kinet. Mech., 41 (2016) 345–355.
[19] F. Labrie, Mechanism of action and pure antiandrogenic properties of flutamide. Cancer., 72 (1993) 3816–3827.
[20] C.P. Firme and P.R. Bandaru, Toxicity issues in the application of carbon nanotubes to biological systems. Nanomed. Nanotechnol. Biol. Med., 6 (2010) 245–256.
[21] T. Tsuneda, J.W. Song, S. Suzuki and K. Hirao, On Koopmans’ theorem in density functional theory. J. Chem. Phys., 133 (2010) 174101.
[22] T. Koopmans, About the assignment of wave functions and eigenvalues to the individual electrons of an atom. Physica., 1 (1934) 104–113.
[23] A.D. Becke, Density‚Äźfunctional thermochemistry. III. The role of exact exchange. J. Chem. Phys., 98 (1993) 5648–5652.
[24] C. Lee, W. Yang and R.G. Parr, Development of the Colle-Salvetti correlation- energy formula into a functional of the electron density. Phys. Rev. B., 37 (1988) 785.
[25] M Frisch, G.W. Trucks, H.b. Schlegel, et al., Gaussian Inc,
Wallingford, CT (2004).
[26] A. Morsali, Mechanism of the Formation of Palladium(II) Maleate Complex: A DFT Approach, Int. . Chem. Kinet., 47 (2015) 73–81.
[27] J. Tomasi and M. Persico, Molecular interactions in solution: an overview of methods based on continuous distributions of the solvent. Chem. Rev., 94 (1994) 2027–2094.
[28] M. Zaboli and H. Raissi, A combined molecular dynamics simulation and quantummechanics study on mercaptopurine interaction with the cucurbit[6,7] urils: Analysis of electronic structure. Spectrochim. Acta. Part A. Mol. Biomol. Spectrosc., 188 (2018) 647–658.
[29] A.E. Reed, J.E. Carpenter and F. Wienhold, NBO version 3.1. Gaussian. Inc Pittsburgh (1992).
[30] F. Biegler-König and J. Schönbohm, AIM2000- A Program to Analyze and Visualize Atoms in Molecules. J. Comput. Chem., 23 (2002) 1489–1494.
[31] D. Yildiz and U. Bozkaya, Assessment of the extended Koopmans' theorem for the chemical reactivity: accurate computations of chemical potentials, chemical hardnesses and electrophilicity indices. J. Comput. Chem., 37 (2016) 345–353.
[32] R.G. Pearson, Absolute Electronegativity and Hardness: Application to Inorganic Chemistry. Inorg. Chem., 27 (1988) 734–740.
[33] P. Bagaria, S. Saha, S. Murru, et al., A comprehensive decomposition analysis of stabilization energy (CDASE) and its application in locating the ratedetermining step of multi-step reactions. Phys. Chem. Chem. Phys., 11 (2009) 8306–8315.
[34] A. Sarmah and R.K. Roy, Understanding the interaction of nucleobases with chiral semiconducting single-walled carbon nanotubes: an alternative theoretical approach based on density functional reactivity theory. J. Phys. Chem. C., 117 (2013) 21539–21550.
[35] N.M. O’boyle, A.L. Tenderholt and K.M. Langner, a library for packageindependent computational chemistry algorithms. . Comput. Chem., 29 (2008) 839–845.
[36] M. Kamel, H. Raissi and A. Morsali, Theoretical study of solvent and co-solvent effects on the interaction of Flutamide anticancer drug with Carbon nanotube as a drug delivery system. J. Mol. Liq., 248 (2017) 490-500.
[37] M. Shahabi and H. Raissi, Assessment of solvent effects on the inclusion behavior of pyrazinamide drug into cyclic peptide based nanotubes as novel drug delivery vehicles. J. Mol. Liq., 268 (2018) 326–334.
[38] M. Kamel, H. Raissi, A. Morsali and K. Mohammadifard, Density functional theory study towards investigating the adsorption properties of the γ-Fe2O3 nanoparticles as a nanocarrier for delivery of Flutamide anticancer drug. Adsorption., (2019) 1–15.
[39] I. Rozas, I. Alkorta and J. Elguero, Behavior of ylides containing N, O, and C atoms as hydrogen bond acceptors. J. Am. Chem. Soc., 122 (2000) 11154–11161.
[40] E. Espinosa and E. Molins, Retrieving interaction potentials from the topology of the electron density distribution: the case of hydrogen bonds. J. Chem. Phys., 113 (2000) 5686–5694.
[41] E. Espinosa, M. Souhassou, H. Lachekar and C. Lecomte, Topological analysis of the electron density in hydrogen bonds. Acta. Crystallogr. Sect. B. Struct. Sci., 55 (1999) 563–572.
[42] J. Contreras-Garc, ER. ohnson, S. Keinan, et al., NCIPLOT: a program for plotting non-covalent interaction regions. J. Chem. Theory. Comput., 7 (2011) 625–632.
[43] H. Hashemzadeh and H. Raissi, Covalent Organic Framework
as Smart and High Efficient Carrier for Anticancer Drug Delivery: A DFT Calculations and Molecular Dynamics Simulation Study. J. Phys. D. Appl. Phys., 51 (2018) 345401.
[44] M. Hesabi and R. Behatmanesh-Ardakani, Investigation of Carboxylation of Carbon Nanotube in the Adsorption of Anti-
cancer Drug: A theoretical approach. Appl. Surf. Sci., 427 (2018) 112–125.
[45] C. Xiong and C. Yao, Adsorption Behavior of MWAR Toward Gd(III) in Aqueous Solution. Iran. J. Chem. Chem. Eng., 29 (2010) 59–66.