Metronidazole (Met.) is an anti-protozoan and positive/negative gram anti-bacterial drug. That is used against the bacterial diseases such as liver, stomach and skin infections, joints, brain, and breathing organ. In addition, it is delivered for various types of stomach ulcers. It is applied for the outside intestine amoebiasis treatment. It has not shown a significant effect on intestinal parasites, so it must be applied along with an intestinal amoebae for inhibition of the infection. Metronidazole effectively eradicates infections in intestinal and extra hepatic tissues .
Molecular interactions of the drugs are of importance in various processes of pharmacology, drug design, imaging, etc. Therefore, the interactions of drugs with the nanomaterials have been extensively studied [2-6]. Employing of the nanostructures as drug delivery carriers is one of the most mentioned items in this area. Nanostructures can be considered as a very effective drug delivery system which can increase the drug efficiency due the following reasons: biocompatibility; ability to slowly release the drug in a controlled manner; protection of the drug’s molecular structure; being smaller than the cell; increasing the drug’s shelf life; reducing the dose required for the patient. Carbon nanostructures such as nanotubes, graphene, and fullerenes have received an extensive attention in pharmaceuticals science. Due to the small size of these nanostructures, they can pass from the membranes easily and insert to the cell [7-9]. In recent years, attention to the computational chemistry has been increased in order to study the drug delivery systems. In fact, the development of drug delivery systems requires deeper studies containing more details [10-15]. In the recent years, fullerenes are one of the nanostructures employed as a drug carrier. However, they have been less investigated by computational methods compared to the other nanomaterials. C30B15N15 Hetero fullerene as a carrier of isoniazid drug and interaction of fullerene doped with 5-fluorouracil drug are some of the studies which have been reported by employing density functional theory (DFT) . The drug must be protected from any chemical and enzymatic degradations before arriving to the target. Doping of the nanostrucures with different functional groups is one of the common methods to increase its specific surface area. Therefore, some researchers have attempted to increase the charge capacity of drugs by doping of the nano materials. For example, Khodadadi et al. utilized nitrogen-doped graphene quantum dots to deliver methotroxate anticancer drug. Their results showed that the quantum dots of graphene doped with nitrogen improve the drug performance [17, 18].
In this research, Gauss View software was used to design Met., pristine C60, and doped with Si-, B-, and Al-doped C60 and their complexes. The energies of the highest occupied and the lowest unoccupied molecular orbitals (HOMO & LUMO), gap energy (Eg) and general characteristics such as chemical potential (μ), chemical hardness (η), maximum charge transfer (∆Nmax), electrophilicity index (ω), etc. were calculated. [19-25].
MATERIALS AND METHODS
The configuration optimizing of all structures were performed with Gaussian 09  in theoretical level of B3LYP/6-31G (d,p). For this purpose, Met. (Fig. 1) was attached to prior C60 and Si-, B-, and Al-doped C60 in different sites with the C, N, and O atoms which are abbreviated as C-Met, N-Met, and O-Met, respectively. All of these three ways have been evaluated in this work. For the recognition of the best interaction sites, molecular electrostatic potential (MEP) calculations were carried out on all of the structures. The HOMO-LUMO values were also extracted from the Gaussian 09 output.
Adsorption energy (Eads.) of Met-Nanocarriers was calculated using the following equation:
Eads.= [Ecomplex]-[ Ecage+ EMet.] (1)
Where EMet, Ecomplex, and Ecage are the energies of Met., fullerene- drug complexes, and pristine fullerene, doped fullerene with silicone, boron, and aluminum, respectively.
In order to evaluate the nanocarrier, drug and complex reactivity, quantum descriptors such as global hardness (η), chemical potential (μ), electrophilicity index (ω), maximum charge transfer (∆Nmax), electronegativity (χ) and Fermi level (EFL) were calculated. These indexes were estimated through the following equations:
In these equations, EHOMO and ELUMO refer to the energies of HOMO and LUMO, respectively. IP and EA show the ionization and electron affinity energies. In addition, the thermodynamic parameters (∆Hads., ∆Sads., ∆Gads.) were calculated to evaluate the drug adsorption possibility by the carriers [27, 28].
RESULTS AND DISCUSSIONS
Several feasible configurations were chosen for approaching of Met. to the fullerene cage. For this purpose, MEP calculations were carried out on drug, nanocages, and their complexes, in which red and blue colors present the regions with high (more nucleophilic) and low (more electrophilic) density electron, respectively. MEP calculations on the molecular surfaces of an individual Met. molecule are shown that O and N atoms may be considered as feasible active sites potentially (Fig.2). On the other hand, the CH3 group in drug is indicated with the blue color presenting a high electron affinity. In the doped fullerene, the blue regions observed for Al-doped C60 is more intensive than those for Si- and B-doped C60. This despite the fact that distribution of MEP is also changed to interaction cage-C60 with Met.
The dipole moment plays a key role in the solubility. In fact, the overall polarity and solubility in water is increased for these nanocages-drug complexes when the dipole moment is increased (Table 1). Since water is the main part of the body, these conclusions suggest that the doping may modify fullerenes drug delivery. As presented in Table 1, C60 has a zero value of dipole moment suggesting it is a non-polar molecule. Doping of the fullerene with the Si, B and Al atoms leads to a significant change in the dipole moment. The metronidazole drug presents a dipole moment value of 4.34 Debye, while the C59Al-C-Met nanocage shows the highest one.
In the next step, the bond lengths between drug and nanocarriers were calculated from optimized structures. The results suggested that the bond length for Met-C60 is lower than that for Met-cages (Table 1). C59Al-C-Met shows the greatest amounts for bond length. In all cases, the bond length for O-cage is lower than that for C- and N-cages. Because the oxygen atom is the more electronegative than, the carbon and nitrogen atoms.
The stability of the drug-nanocarrieres were evaluated by calculation of the adsorption energy (Table 2). The results showed that when Met. with the nanocages, adsorption energies will be become negative. While, these values for undoped-C60 are very low. Thus, adsorption of the drug is almost unstable on the undoped fullerene from the C-, N-, and O- sites. Finally, negative adsorption energies of drug-doped nanocages leads to an increase in the stability. The highest adoption energy was observed in the C59Si-O-Met system (-61.73 kcal mol-1). Then, the thermodynamic parameters were calculated to investigate the drug adsorption possibility from energetic point of view (Table 2). It is clear that, all of Gibbs free energies values are negative in value except for the C60-C-Met and C60-N-Met systems. This suggests that adsorption of Met. on the Si-, B-, and Al-nanocarriers is spontaneous. The C59Si-O-Met system showed the highest Gibbs free energy. Therefore, it can be concluded that doping leads to enhancement of adsorption performance. Adsorption enthalpy values are negative in value for all complexes except for the C60-C-Met and C60-N-Met systems. This illustrates that the drug adsorption process is exothermic. The C59Si-O-Met system presented the highest enthalpy (-59.60 kcal mol-1). In all systems, the adsorption entropy is negative in value, which shows that the drug adsorption process takes place with decreasing of disorder in agreement with the adsorption mechanism.
Calculation of the HOMO and LUMO orbital images of the drug, pure and doped C60 and drug–doped complexes showed that these orbitals are located on the ring and the NO2 groups (S-1). In addition, the frontier molecular orbitals of the C60 fullerene are almost symmetric. In the doped fullerenes, density of orbitals on the doped atom is higher than the other ones (specially for the Al-nanocages). HOMO orbitals in C59Si-N-Met and C60-N-Met and LUMO orbitals in C59Al-N-Met, C59B-N-Met, C59Si-N-Met. systems are and located on the drug and the fullerene cages does not have a share in them. Eg is a quantity that determines the reactivity of a molecule. According to Table 3, Eg of C60 is higher (2.87 eV) than doped-C60: C59Si, C59B, and C59Al with values of 2.24, 2.54, and 2.22 eV, respectively, and thus the doped molecules show higher tendency to chemical interaction with Met.. On the other hands, Eg of Met. equals to 4.35 eV. The value of Eg for drug-nanocages is lower than pure C60 and Met.. Also, the Table presents the values of Eg for N-nanocages: C59-N-Met, C59Si-N-Met, C59B-N-Met, and C59Al-N-Met (0.51, 0.35, 1.46, and 1.04 eV) which are very low compared to the other systems (≈ 2.2-2.7 eV). Fermi level is the highest energy state occupied by electrons in a material at absolute zero temperature. The Fermi levels (EFL) for Met., fullerene, and nanocages are in agreement with the Eg values. In order to better understand the electronic changes in the evaluated systems after drug absorption, density of states (DOS) curves were calculated (Fig. 3).
Chemical potential (μ) values shows the affinity to the electron attraction. The negative values of chemical potential show that the charges transfer between two particles are spontaneously. The electron transfer occurs from a molecule with a higher chemical potential to a molecule with a lower one. In this work, the electronic chemical potentials (μ) for all drug-cage complexes are negative and in the range of -3.7 to -4.95 eV. According to Table 3, the chemical potential of the drug is higher than other compounds, indicating that the electron transfer in the corresponding complexes takes place from the drug to the fullerenes. Hence, increment of the reactivity in the doped fullerene can be concluded with the drug adsorption.
Chemical hardness indicates resistance to change in the electron density of a chemical system, and can explain the system stability. The chemical hardness of fullerene is reduced after doping and also absorption of drug. According to results, chemical hardness has reduced after drug adsorption by doped-C60 from toward the N-site of drug. Table 3 presents that chemical hardness for N- nanocages including C60-N-Met, C59Si-N-Met, C59B-N-Met, and C59Al-N-Met have the lowest values (0.25, 0.18, 0.73, and 0.52 eV, respectively).
In organic chemistry, an electrophile is an electron absorbent, which are in positive or neutral modes. They have certain empty orbitals for electron absorption. When two molecules react each other, one molecule acts as a nucleophile, while the other plays the role of an electrophilic. Electrophilicity power (ω) is a parameter related to HOMO and LUMO that indicates the reactivity of the structure. In fact, the electrophilicity index is the energy stability when the system accepts electrons. In this work, the ω values are high (≈8-38.5 eV) for all of molecules. Also, this parameter is higher for nanocages-N-Met than the other ones (≈15.5-38.5 eV).
The most electrical charge that an electrophilic system can accept is called ΔNmax . In other words, ΔNmax indicates the charge capacity of a molecule. According to the ΔNmax equation (eq. 6), by increasing the chemical potential, the chemical hardness is decreased and the electrophilicity power is increased. When the system possesses more electron deficiencies, it becomes more positive, and thus, it is expected that the possibility of electron transfer to the system is increased. The results related to ΔNmax (Table 3) show that the level of this parameter in N-nanocages-Met is higher than the other molecules (≈6.5-20.6 eV). The results suggest that by attachment of Met. to the nanocages from toward nitrogen site has higher values of electrophilicity and electrical charge compared to the two other alternative ways (carbon and oxygen sites).
We performed DFT calculations to study interactions of the C60 fullerene with Metronidazole Drug. Furthermore, Si-, B-, and Al-doped C60 fullerenes were also studied. All of possible interactions drug to nanocages from different towards (C-, N, and O-) are carried out and finally, following results were extracted:
The MEP images displayed that the reigns containing O and N in the metronidazole drug have the affinity to the nucleophile role in the reaction. While, the CH3 group has the affinity to play the electrophile role in the reaction. Doping of the fullerene with the Si, B and Al atoms leads to perceptible changes in the dipole moment. The C59Al-C-Met nanocage has the highest value of dipole moment. In all nanocages-Met, bond length of O-cage is lower than that of C- and N-cages due to the more electronegativity of oxygen compared to the carbon and nitrogen atoms. The negative adsorption energies of drug-doped nanocages leads to increasing their stability. The highest adsorption energy was shown in the C59Si-O-Met system (-61.73 kcal mol-1). These results confirm that the adsorption of Met. on the Si-, B-, and Al-nanocarriers are spontaneous. The C59Si-O-Met system showed the highest Gibbs free energy. The value of Eg for drug-nanocages is lower than that for pure C60 and Met.. Also, the values of Eg for N- nanocages C59-N-Met, C59Si-N-Met, C59B-N-Met, and C59Al-N-Met were found to be 0.51, 0.35, 1.46, and 1.04 eV, respectively, which are very low compared to the other systems (≈2.2-2.7 eV). Chemical potential (μ) for all drug-cages are negative in range of -3.7 to -4.95 eV. Chemical hardness has reduced after drug adsorption by doped-C60 from toward the N-site of drug. The ω parameters for all of the molecules is high (≈8-38.5 eV). Also, this parameter for nanocages-N-Met is higher than other cages (≈15.5-38.5 eV).
It can be concluded as a general perspective that doping of C60 with Si, B, and Al atoms improves the C60 performance as a nanocarrier in drug delivery systems.
CONFLICTS OF INTEREST
The authors do not have any personal or financial conflicts of interest.