Chloroquine drug and Graphene complex for treatment of COVID-19

This paper is a new step in helping the treatment of coronavirus by improving the performance of chloroquine drug. For this purpose, we propose a complex of chloroquine drug with graphene nanoribbon (GNR) scheme. We compute the structural and electrical properties and absorption of chloroquine ( C 18 H 26 ClN 3 ) and GNR complex using the density functional theory (DFT) method. By creating a drug and GNR complex, the density of states of electrons increases and the energy gap decreases compared to the chloroquine. Also, using absorption calculations and spectrums such as infrared and UV-Vis spectra, we showed that GNR is a suitable structure for creating chloroquine drug complex. Our results show that the dipole moment, global softness and electrophilicity for the drug complex increases compared to the non-complex state. Our calculations can be useful for increasing performance and reducing the side effects of chloroquine, and thus can be effective in treating coronavirus. length of optimized chloroquine drug-GNR complex


Introduction
In the end of 2019, in China, a virus similar to human coronaviruses, SARS and MERS 1-4 pneumonia, was reported, later called COVID-19 5,6 . According to the World Health Organization (WHO), in April 2020, more than 2 million cases of the virus and about 150,000 deaths were reported 7 . Recently, with the appearance and increase of coronavirus epidemic in many countries, chloroquine has become a major drug in the treatment of coronavirus. [8][9][10][11] . In the past years, chloroquine drug was used to therapy and control of malaria 8,11,12 . Recent studies have shown that this drug successfully treats patients with coronavirus pneumonia 11 . Also, the chloroquine drug has potential applications in the treatment of diseases such as rheumatoid arthritis (RA) 13 , systemic lupus erythematosus (SLE) [14][15][16] , antiphospholipid syndrome (APS) 17 and primary Sjogren syndrome 18 . Previous studies have shown that chloroquine has an antiviral mechanism and by increasing the pH, it prevents unwanted viruses such as human immunodeficiency virus (HIV) 19 , Zika virus 20,21 , Ebola virus 22 and the avian leucosis virus 23 from entering the cell. Also, chloroquine can prevent the virus gene from multiplying by increasing the pH 24,25 . To increase the effectiveness of chloroquine and to increase special cellular uptake and reduce nonspecific gathering in the vivo tissues, the design of drug delivery systems for chloroquine drug is required. The drug delivery systems can control the drug release in vivo and increase performance encapsulation and absorption 26,27 . Nanomaterial-based drug delivery systems have π − π stacking interactions or covalent crosslinking with drug molecules due to their small size [28][29][30][31] . Graphene, as a member of nanomaterials with a two-dimensional structure with strong π − π stacking bond 32 , has unique physical, chemical and optical properties. For this reason, graphene was noticed in biomedical issues such as drug delivery [33][34][35] and biosensors 36,37 . This drug is consumed orally and absorbed in most vivo tissues which increases side effects and reduces the performance of the chloroquine in lung tissue. But by combining this drug, the possibility of passing through every tissue is reduced. Therefore, the side effects of the drug are reduced and the effectiveness of the drug in the vivo tissues is increased. Any previous research on chloroquine and GNR complex has not been performed. Therefore, a study of the electrical and structural properties of chloroquine with graphene is essential for drug delivery vivo. In this paper, we theoretically examine the absorption and electrical and structural properties of chloroquine attached to graphene nanoribbon (GNR), which has potential applications in drug delivery. are based on the density functional theory (DFT) and were performed by using Gaussian 09 (G09) program package 38 . In this work, the exchange and correlation energy function is performed by applying the B3LYP method in G09 39,40 . To study the electrical and structural properties of the system, we use the 3-21 g basis set 41,42 . In Ref. 43, good results have been obtained by B3LYP method with long-range correlations. Using the results of the frequency calculations and optimized structures, we determined the absorption energy for chloroquine-GNR complex. Then, we calculated the electronic properties of chloroquine and GNR. We introduced E LOMO , the lowest unoccupied molecular orbital (LUMO) energy, and E HOMO , the highest occupied molecular orbital (HOMO) energy, defined as E gap = E LUMO − E HOMO and E F = (E LUMO + E HOMO ) 2 44 in which E gap and E F are the energy gap and Fermi energy respectively (all listed in Table 1).
We describe another parameters such as: the chemical potential (µ), chemical hardness (η), global softness (S) and electrophilicity index (ω), which may be written as 45 : (1) Absorption energy can be obtained using the following relations 45,46 : where E G , E D and E G−D are GNR energy, the drug molecule energy and chloroquine-GNR complex energy respectively.

Results and discussion
In this section, we study the electron density of states, IR and UV-Vis spectrums in optimized GNR structures, chloroquine and complex of chloroquine-GNR. We considered GNR and chloroquine drug with the chemical formula of C 20 H 12 and C 18 H 26 ClN 3 respectively. Our calculations show that the best position of chloroquine drug to interact with GNR is N-terminal of drug ( Figure 1), because the energy of absorption is almost the same as the amount of energy absorbed by applying the counterpoise correction.
We obtained the optimized geometrical structures of the drug, GNR and complex of chloroquine-GNR. The bond length of atoms of chloroquine drug and chloroquine-GNR nanostructures are explained in the Table 1.

Chloroquine-GNR Complex
In this section, we obtained the structural properties of the complex chloroquine drug and GNR. Table 1 Table 2.

Electronic properties
In this section, we are going to describe the electrical properties of the mentioned system. The density of state (DOS) versus the incident electron energy are shown in Figure 2 using the GaussSum 3.0.2 program for GNR, chloroquine and chloroquine-GNR complex. Figure 2 shows that for GNR there is a large energy gap between HOMO and LUMO, while for chloroquine the energy gap is smaller than that of GNR. Clearly, the DOS is very highlighted in the vicinity of Fermi energy in chloroquine drug. As it is shown, the sharpness of peaks in GNR is reduced compared to the drug. DOS for GNR has also increased compared to drug. Thus, electron conductance for chloroquine has decreased. The energy gap of the drug and GNR complex is reduced compared to the drug and GNR. But the electron conductance in the drug and GNR complex is increased in comparison to the GNR and chloroquine. Also in DOS profiles the sharpness of peaks, in chloroquine-GNR complex, are highlighted compared to GNR.
Our calculations for E LUMO , E HOMO , energy gap, Fermi energy and dipole moment are reported in Table 3. Table 3 shows that the energy gap for GNR and chloroquine are 3.14 (eV) and 1.48 (eV) respectively that is more for GNR than the drug. Also, the energy gap of the chloroquine-GNR complex is 1.28 (eV), which is reduced compared to GNR and drug separately. It is clear that the dipole moment for the drug is much higher than that of GNR. The dipole moment has increased in the case of the chloroquine-GNR complex compared to chloroquine and GNR separately.
The LUMO and HOMO orbitals for chloroquine-GNR complex are shown in Figure 3. It is observed that the population of LUMO and HOMO orbitals are in (RS) − N − (7 − chloroquinolin − 4 − yl) − pentane − 1 − amine and N-terminal, respectively.

Stability properties
In this section, we obtained the infrared spectra (IR) and UV-Vis spectrums of the GNR, chloroquine and chloroquine-GNR complex, and to determine their stability, we drew the real part of the frequency vibrations 47 . Figure 4 shows the IR spectrum for GNR, chloroquine and chloroquine-GNR complex. The IR spectrum includes parameters such as frequency, ε (wave energy levels) and dipole strength (D). Absorption for GNR, chloroquine and the complex occurs in the range of 500-3000 (cm −1 ), 500-2300 (cm −1 ) and 500-2300 (cm −1 ) respectively. Also, the maximum vibrational frequency for GNR, chloroquine and complex occurs in 840 (cm −1 ), 703.76 (cm −1 ) and 700 (cm −1 ) respectively. Therefore, as the GNR and drug are combined, the maximum vibration frequency is reduced. Figure 5 shows the UV-Vis spectrums of the incident parameters versus the wavelength, ε and oscillator strength for GNR, chloroquine and chloroquine-GNR complex. In UV-Vis spectrums the absorption index for GNR, chloroquine and complex are in the range of 283-585 (nm), 584-3000 (nm) and 688-2536 (nm) respectively. The maximum vibration frequency for GNR, chloroquine and complexes occur in 411 (nm), 1235 (nm) and 1024 (nm) respectively.

Electrochemical properties
Here, we study the electrochemical properties of GNR, chloroquine and chloroquine-GNR complex. The parameters investigated include the chemical potential (µ), chemical hardness (η), global softness (S) and electrophilicity index (ω) which are listed in Table 4. Chemical potential calculations show that the chloroquine drug is more negative than GNR. Both values of the ionization energy (IP) and electron affinity (EA) are positive. Also, ionization energy and electron affinity are more negative for the drug than GNR due to the fact that HOMO and LUMO levels are more negative. According to Table 4, the chemical hardness for chloroquine is smaller than the GNR due to the small difference between the levels of LUMO and HOMO. Because the chemical hardness values for GNR are higher than those for the drug, the global softness for GNR is smaller compared to the chloroquine. It is observed that the electrophilicity index for chloroquine drug is more stronger than that of GNR. The reason for this increase in the drug is the large amount of chemical potential. We see that in the chloroquine-GNR complex, other parameters are reduced except for global softness and electrophilicity index. In other words, amount of global softness and electrophilicity for the chloroquine-GNR complex has increased compared to the drug and GNR separately. Using Eq. (7), the GNR absorption values in chloroquine drug are obtained as 7.9 (k j mol) or 1.88 (kcal mol). GNR is absorbed in chloroquine due to its positive absorption values.   Table 4. Electrochemical properties of the introduced chloroquine, GNR and chloroquine-GNR complex.

Conclusion
Using the DFT method, we numerically evaluated the electrical, structural, and adsorption properties for optimized graphene nanoribbon (GNR), chloroquine, and chloroquine-GNR complex nanostructures. The density of state calculations illustrate that the energy gap for the chloroquine-GNR complex is reduced relative to the GNR and drug, and the electron conductance is increased. Our results show that parameters such as dipole moment, global softness and electrophilicity increase with the formation of complex. Examination of the infrared spectra and UV-Vis spectrums of the absorption spectra indicates that GNR is absorbed in the chloroquine drug. We have shown that GNR nanostructures are suitable for complexes with chloroquine drug and can be very effective in the drug delivery of chloroquine and therefore help treat COVID-19.