Thermodynamic and reactivity descriptors Studies on the interaction of Flutamide anticancer drug with nucleobases: A computational view

Document Type : Research Article


1 Department of Chemistry, Payame Noor University, PB BOX 19395-4697 Tehran, Iran

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


< p>In this work, the interaction between Flutamide (FLU) anticancer drug with nucleobases such as cytosine, thymine, uracil, and adenine was studied by density functional theory (DFT) methods from a thermodynamic point of view. The Gibbs free energy (ΔG) and enthalpy (ΔH) of C-FLU, T-FLU, U-FLU and A-FLU complexes were computed and demonstrate that the stronger interaction between cytosine and FLU and the adsorption of the drug on the bases proceeds spontaneously. The negative value of ΔH indicates that the adsorption of FLU drug on the cytosine, thymine and uracil bases are exothermic, these results confirmed ΔE results. During the interaction of Flutamide drug with nucleobases, the energy levels of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were significantly changed. The values of the energy gap (Eg) reduced during the adsorption of the FLU drug onto bases which confirmed that the reactivity of the resulted complex increase upon adsorption. On the other hand, as a result of theoretical calculations, the values of the Eg for the Base-FLU structures in water solution are decreased in comparison to the corresponding values in the gas phase, indicating more the reactivity of the studied complexes in the aqueous medium.

Graphical Abstract

Thermodynamic and reactivity descriptors Studies on the interaction of Flutamide anticancer drug with nucleobases: A computational view


Main Subjects

[1] S.C.B. Oliveira, A.M. Chiorcea-Paquim, S.M. Ribeiro, A.T.P. Melo, M. Vivanc and A.M. Oliveira Brett, Bioelectrochemistry, 76 (2009) 201-207.
[2] S. Raufa, J.J. Gooding, K. Akhtar, M.A. Ghauria, M. Rahman, M.A. Anwar and A.M. Khalid, Electrochemical approach of anticancer drugs–DNA interaction. J. Pharm. Biomed. Anal., 37 (2005) 205-217.
[3] L. Xiangqin, X. Jiang and L. Lu, DNA deposition on carbon electrodes under controlled dc potentials. Biosens. Bioelectron. 20 (2005) 1709–1717.
[4] L. Xiaoquan, Y. Chen, J. Chen, Y. Zhang, L. Zhang and M. Li, Electrochemical studies of the interaction of quercetin with DNA. Int. J. Electrochem. Sci., 1 (2006) 130–138.
[5] G.M. Cragg, D.J. Newman and K.M. Snader, Natural products in drug discovery and development. J. Nat. Prod., 60 (1997) 52-60.
[6] V.R. Palwai and L.A. Eriksson, Molecular dynamics simulations exploring the interaction between DNA and metalated bleomycin. J. Biophys. Chem., 2 (2011) 170-182.
[7] M. A. Khusenov, E. B. Dushanov and Kh. T. Kholmurodov, Molecular Dynamics Simulations of the Nucleotides and Metallic Nanoparticles Interaction on a Carbon Nanotube Matrix. Mater. Trans., 56 (2015) 1390-1393.
[8] P.K. Brahman, R.A. Dar and K.S. Pitre, Voltammetric study of ds-DNA–flutamide interaction at carbon paste electrode. Arab. J. Chem., 9 (2016) 1884-1888.
[9] A. Snycerski, Polarographic determination of flutamide. J. Pharm. Biomed. Anal., 7 (1989) 1513-1518.
[10] F. Vargas, C. Rivas, H. Mendez, A. Fuentes, G. Fraile and M. Velas, J. Photochem. Photobiol. B: Biol., 58 (2000) 108–114.
[11] O. Payen, S. Top, A. Vessières, E. Brulé, A. Lauzier, M.A. Plamont, M.J. McGlinchey, H.M. Bunz and G. Jaouen, J. Organomet. Chem. 696 (2011) 1049–1056.
[12] M. Kamel, H.Raissi, H. Hashemzadeh and K.Mohammadifard, Understanding the role of hydrogen bonds in destruction of DNA by screening interactions of Flutamide anticancer drug with nucleotides bases: DFT perspective, MD simulation and free energy calculation. Adsorption, 26 (2019) 1–18.
[13] M.J. Frisch, G.W. Trucks, H.b. Schlegel, et al., Gaussian Inc, Wallingford, CT (2004)
[14] Y. Zhao and D.G. Truhlar, The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other function. Theor. Chem. Acc., 120 (2008) 215–241.
[15] M.J. Frisch, J.A. Pople and J.S. Binkley, Self-consistent molecular orbital methods 25. Supplementary functions for Gaussian basis sets. J. Chem. Phys. 80 (1984) 3265–3269.
[16] S. Miertuš, E. Scrocco and J. Tomasi, Electrostatic interaction of a solute with a continuum. A direct utilizaion of AB initio molecular potentials for the prevision of solvent efects. Chem. Phys., 55 (1981) 117–129.
[17] M. Kamel, H.Raissi, H. Hashemzadeh and K.Mohammadifard, Theoretical elucidation of the amino acid interaction with graphene and functionalized graphene nanosheets: insights from DFT calculation and MD simulation. Amino Acids, 52 (2020) 1465-1478.
[16] M. Kamel, A. Morsali, H. Raissi and K. Mohammadifard, Theoretical insights into the intermolecular and mechanisms of covalent interaction of Flutamide drug with COOH and COCl functionalized carbon nanotubes: A DFT approach. Chem. Rev. Lett., 3 (2020) 23-37.
[17] L.R. Domingo, E. Chamorro and P. Pérez, Understanding the reactivity of captodative ethylenes in polar cycloaddition reactions. A theoretical study. J. Org. Chem., 73 (2008) 4615–4624.
[18] P. Jaramillo, L.R. Domingo, E. Chamorro, P. Pérez, A further exploration of a nucleophilicity index based on the gas-phase ionization potentials. J. Mol. Struc-THEOCHEM., 865 (2008) 68–72.
[19] I. Fleming, Frontier Orbitals and Organic Chemical Reactions, John Wiley and Sons, New York, 1976.
[20] G. Mariappan and N. Sundaraganesan, Spectral and structural studies of the anti-cancer drug Flutamide by
density functional theoretical method. Spectrochim. Acta A Mol. Biomol. Spectrosc. 117 (2014) 604–613.
[21] R.G. Parr and R.G. Pearson, Absolute hardness: companion parameter to absolute electronegativity. J. Am. Chem. Soc., 105 (1983) 7512–7516.
[22] R.G. Parr, R.A. Donnelly, M. Levy and W.E. Palke, Electronegativity: the density functional viewpoint. J. Chem. Phys., 68 (1978) 3801.
[23] 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.
[24] R.G. Pearson, Absolute Electronegativity and Hardness: Application to Inorganic Chemistry. Inorg. Chem., 27 (1988) 734–740.
[25] M. Kamel, H. Raissi, A. Morsali and M. Shahabi, Assessment of the adsorption mechanism of Flutamide anticancer drug on the functionalized single-walled carbon nanotube surface as a drug delivery vehicle: An alternative theoretical approach based on DFT and MD. Appl. Surf. Sci., 434 (2018) 492–503.
[26] P. Bagaria, S. Saha, S. Murru, V. Kavala, B.K. Patel and R.K. Roy, A comprehensive decomposition analysis of stabilization energy (CDASE) and its application in locating the rate-determining step of multi-step reactions. Phys. Chem. Chem. Phys., 11 (2009) 8306–8315.
[27] A. Sarmah, S. Saha, P. Bagaria and R.K. Roy, On the complementarity of comprehensive decomposition analysis of stabilization energy (CDASE) - scheme and supermolecular approach. Chem. Phys., 394 (2012) 29–35.
[28] N.M. O''Boyle, A.L. Tenderholt and K.M. Langner, A library for package-independent computational chemistry algorithms. J. Comput. Chem., 29 (2008) 839–845.
[29] S.A. Siadati, M.S. Amini-Fazl and E. Babanezhad, The possibility of sensing and inactivating the hazardous air pollutant species via adsorption and their [2 + 3] cycloaddition reactions with C20 fullerene Sensors and Actuators B: Chemical, 237 (2016) 591-596.
[30] E. Vessally, S. A. Siadati, A. Hosseinian and L. Edjlali, Selective sensing of ozone and the chemically active gaseous species of the troposphere by using the C20 fullerene and graphene segment. Talanta., 162 (2017) 505-510.
[31] S.A. Siadati, E. Vessally, A. Hosseinian, L. Edjlali, Possibility of sensing, adsorbing, and destructing the Tabun-2D-skeletal (Tabun nerve agent) by C20 fullerene and its boron and nitrogen doped derivatives, Synthetic Metals, 220 (2016) 606-611.
[32] S.A. Siadati, K. Kula and E. Babanezhad, The possibility of a two-step oxidation of the surface of C20 fullerene by a single molecule of nitric (V) acid, initiate by a rare [2+3] cycloaddition. Chemical Review and Letters, 2 (2019) 2-6.
[33] T.M. Gogary and G. Koehler, Interaction of psoralens with DNA-bases (I). An ab initio quantum chemical, density functional theory and second-order Møller–Plesset perturbational study. J. Mol. Struct. THEOCHEM., 808 (2007) 97–10.
[34] N.S. Venkataramanan, A. Suvitha and Y. Kawazoe, Intermolecular interaction in nucleobases and dimethyl sulfoxide/water molecules: a DFT, NBO, AIM and NCI analysis. J. Mol. Graph. Model., 78 (2017) 48–60.
[35] 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., 26 (2020) 925–939.
[36] Shabani, M, Ghiasi, R, Zarea and K; Fazaeli, R, Quantum Chemical Study of Interaction between Titanocene Dichloride Anticancer Drug and Al12N12 Nano-Cluster. Russ. J. Inorg. Chem., 65 (2020) 1726-1734.
[37] M. Shahabi and H. Raissi, Investigation of the molecular structure, electronic properties, AIM, NBO, NMR and NQR parameters for the interaction of Sc, Ga and Mg- doped (6,0) aluminum nitride nanotubes with COCl2 gas by DFT study. J. Incl. Phenom.Macrocycl. Chem., 84 (2016) 99–114.
[38] MS. Hoseininezhad-Namin, P. Pargolghasemi, S. Alimohammadi, AS. Rad and L. Taqavi, Quantum Chemical Study on the adsorption of metformin drug on the surface of pristine, Si- and Al-doped (5, 5) SWCNTs. Physica E., 90 (2017) 204–213.
[39] J. Aihara, Reduced HOMO− LUMO gap as an index of kinetic stability for polycyclic aromatic hydrocarbons. J. Phys. Chem. A., 103 (1999) 7487-7495.
[40] Z. Kazemi, R. Ghiasi and S. Jamehbozorgi, The interaction of 5 fuorouracil with graphene in presence of external electric feld: a theoretical investigation. Adsorption, 26 (2020) 905-911.
[41] Z. Kazemi, R. Ghiasi and S. Jamehbozorgi, Analysis of the Interaction Between the C20 Cage and cis-Ptcl2(NH3)2: A DFT Investigation of the Solvent Effect, Structures, Properties, and Topologies. J. Struct. Chem., 59 (2018) 1044-1051.