key: cord-0927559-ad6fyh15
authors: Rad, Ali Shokuhi; Ardjmand, Mehdi; Esfahani, Milad Rabbani; Khodashenas, Bahareh
title: DFT calculations towards the geometry optimization, electronic structure, infrared spectroscopy and UV-vis analyses of Favipiravir adsorption on the first-row transition metals doped fullerenes; a new strategy for COVID-19 therapy
date: 2020-10-17
journal: Spectrochim Acta A Mol Biomol Spectrosc
DOI: 10.1016/j.saa.2020.119082
sha: 902808a2fa5d31d62ab09ee61d5df26e9af9daa7
doc_id: 927559
cord_uid: ad6fyh15

With the global epidemic of the COVID-19 virus, extensive and rapid research on drug therapy is underway around the world. In this regard, one of the most widely studied drugs is Favipiravir. Our aim in this paper is to conduct comprehensive research based on the Density Functional Theory (DFT) on the potential of metallofullerenes as suitable drug carriers. The surface interaction of Favipiravir with organometallic compound resulted by doping of the five transition metals of the first row of the periodic table (Ti, Cr, Cr, Fe, Ni, and Zn) was examined in depth to select the most suitable metallofullerenes. First, the adsorption geometries of Favipiravir drug onto each metallofullerene were deeply investigated. It was found that Cr-, Fe-, Ni-doped fullerenes provide the excellent adsorbent property with adsorption energies of -148.2, -149.6, -146.6 kJ/mol, respectively. The Infrared spectroscopy (IR) study was conducted to survey the stretching vibration of bonds involving in the systems, specialty the C=O in the drug, C-M in the metallofullerene, and M-O in the metallofullerene-drug complex. Finally, the UV-vis analysis showed that the absorption spectra for the studied systems may be attributed to the transition from π-π * and/or n - π*.

The widespread coronavirus infection 2019 produced by SARS-CoV-2 that begun in Dec. 2019, is one of those worldwide challenges that transcends territorial, political, ideological, religious, cultural, and definitely academic borders. 1 No established medical effectiveness of antiviral substrate for COVID-19 has been discovered by this time, whereas specific drugs, including Favipiravir, Remdesivir, Chloroquine, and Arbidol are presently under intensive investigation for the treatment of COVID-19. 2, 3 Favipiravir is an approved antiviral medicine in Japan for influenza. 4 Comparing the effectiveness of Favipiravir with Arbidol 2 suggest that Favipiravir may be a prospective nominee to cure COVID-19.

According to the results of Chen et al., 2, it can be theorized that Favipiravir could be a suitable medicine for the treatment of COVID-19 based on improving clinical recovery rate on Day 7 and lessening pyrexia, cough, and ARDS. Very recently, it has been found that Favipiravir as a prodrug, excellently prevents the COVID-19 infection in Vero E6 cells (ATCC-1586). 5, 6 Additionally, other investigations display that Favipiravir is an effective drug in keeping mice safe against the Ebola virus trial. 7 So, clinical researches are immediately required to assess the usefulness and security of this antiviral nucleoside against the COVID-19 cure.

Various nanostructures were established extensive applications in drug delivery systems owing to high surface/volume ratio that is noticeably superior compared to that of the conventional microstructures. [8] [9] [10] [11] [12] [13] Among all nanostructures, carbon nanotubes, graphene and fullerenes are prevalent because of their straightforward method of functionalizing and J o u r n a l P r e -p r o o f Journal Pre-proof surface improvement, so that they have been considered extensively as drug carriers. 11, 13, [14] [15] [16] [17] [18] [19] [20] Fullerene and its derivatives have been used as potential carriers towards anticancer medicines owing to have outstanding features such as high loading capability 21 and protecting impact on the heart and liver versus chronic poisonousness resulted from chemotherapeutics. 22 In addition, it was found that fullerene can pass the cell membrane to arrive at the tumor cells, concentrating in the nucleus, lysosomes, and cytoplasm. 23, 24 Among fullerenes, the C 20 is the tiniest structure that has a dodecahedral cage structure. The C 20 was synthesized for the first time by Prinzbach et al. 25 via the gas-phase production method. Further, this kind of fullerene was synthesized through ion-beam irradiation 26 and laser-ablation 27 methods .

The main limiting factor of fullerene family for biological application is their intrinsic hydrophobicity. Towards overcoming this problem, different investigations have been carried out, aiming to find suitable approaches for the production of water-soluble fullerene. These techniques comprise, construction of host-guest complexes that are water-soluble 28 , addition of surfactant 29 , alcoholization 30 , and chemical modification. [31] [32] [33] Amongst these procedures, chemical modification by inserting impure atoms to fullerene showed promising results. [34] [35] [36] Doping through an exterior atom is one of the current approaches for changing the electronic properties of a nano-system. Exo-hedral, endo-hedral and substitutional doping are three different methods by which an exterior atom is hosted. The substitution doping that encompasses substitution of an atom of fullerene through a dopant (transition metal in this J o u r n a l P r e -p r o o f Journal Pre-proof study) is comparatively less investigated than exo-hedral and endo-hedral doping. It has been concluded that substituting a carbon atom of fullerene by a metal atom (resulting in a metallofullerene molecule) is a suitable tactic to advance the drug delivery property by increasing its adsorption potential. 37 For instance, Rad et al. 34, 35 investigated the Cr-and

Ni-doped fullerenes and found significant adsorption of adenine, thymine, and uracil nucleotides on the surface of metal-doped fullerene. In another work conducted by the same group, they found that the potential of cytosine and guanine nucleobases adsorption onto fullerene substantially increases by metal doping. 36 The ideal carrier provide a moderate and controllable release of Favipiravir drug in order to prolong the spread time of the drug and shielding it from abolition by phagocytic cells or early destruction. The idea of the present research of using metallofullerene carrier for Favipiravir is raised from the successful applications of metallofullerene as a drug carrier. [34] [35] [36] [37] In the following research, we aimed to investigate if certain kinds of metallofullerenes are potentially appropriate for the adsorption and keeping of the Favipiravir drug. The experimental investigation on new materials as a drug carrier is essential; however, they are costly, time-consuming and also they cannot provide enough fundamental information in the atom-scale environment. Therefore, computational approaches have been progressively employed to help to understand the mechanism and the nature of the molecule interactions. 38 In the following research, for the first time we investigated the adsorption property of 

The initial geometry optimization of all structures in the ground state was carried out in the water solvent by B3LYP/6-31G level of theory, but to find more accuracy geometry, the output structures were used for next optimization at ωb97xd/6-31+G(d,p) level of theory.

Both levels of theory were implemented in the Gaussian 09 suite of the program. 41 The DFT technique was used owing to the accuracy associated. Vibration frequency calculation was performed for each resulted structure to find out thermodynamical parameters, including enthalpy change (ΔH) and Gibbs free energy change (ΔG) of Favipiravir molecule adsorption process. The frequency calculation revealed that there was no imaginary value in the spectrum, implying the structures were really minima .

The ωb97xd/6-31+G(d,p) has been found as one of the most favorable levels of theory for responsible and precise calculation at minimum cost for fullerene system. 42 The electronic J o u r n a l P r e -p r o o f Journal Pre-proof properties, including the density of states (DOSs), FMO, and NBO charge analysis were calculated at the same level of theory. Following the geometry optimization, the TD-DFT formalism from the ground state at the TD-ωb97xd/6-31++G(d,p) level of theory was used to calculate the excited states to achieve theoretical UV-vis spectra .

To investigate the stability of each metallofullerene (C19M, M=Ti, Cr, Fe, Ni, and Zn), the cohesive energies (E c ) was calculated through the following equation:

Where E C and E M , and E C19M are the energies of a single C atom, a single M atom, and metallofullerene molecule, correspondingly. N is the total numbers of atoms involved in system (here, N=20).

The adsorption energy (E ad ) of Favipiravir molecule onto each metallofullerene (C19M, M=Ti, Cr, Fe, Ni, and Zn) was calculated by equation 2:

Where E C19M/F is the total energy of C 19 M-Favipiravir complex, E C19M is the total energy of metallofullerene, E F is the total energy of the Favipiravir, and E BSSE is the basis set superposition error (BSSE) corrected for all interactions. The enthalpy change (ΔH) and

Gibbs free energy change (ΔG) were calculated at T = 298 K and P = 1 atm by the equations 3 and 4, respectively. The energy gap between HOMO and LUMO (E g ) was well-defined as

Whereas E LUMO and E HOMO are energy of HOMO and LUMO.

The energy of Fermi level (E FL ) that lies in the middle of the HOMO and LUMO was calculated through the equation 6:

It was known that C 20 fullerene has a symmetric structure. It can be anticipated that Table 1 , the average M-C bond length for each system was calculated as attributes to the electron configuration and the effect of d-orbital splitting on the Radii of the studied elements. The obtained trend is in agreement with the experimental results reported by Jin et al. on the complex formation of the first-row transition metals. 46 As depicted in Table 1 , the dimension (D) of the metallofullerene also did not follow any regular pattern. The b3lyp (ωB97XD) calculated diameter of each metallofullerene were 5.04 Ni, and C 19 -Zn, respectively.

The cohesive energies of all metallofullerenes were calculated using the ωB97XD method to compare the stability of all the studied metallofullerenes. As is presented in Table 1 , the E c values show no regular pattern, but they revealed that all the metallofullerenes have stable structures owing to the negative value of cohesive energies. However, they all were relatively less stable than the pure C 20 fullerene (-8.01 eV) as investigated by our group. 47 One can conclude that the decreasing or increasing trend of E c depends on the electrostatic interaction of the transition metal and carbon atoms of the metallofullerene, as the evidence from the charge analysis (vide infra). 1 An average of three X-C bond lengths has been calculated.

It was found that three possible isomers for a Favipiravir molecule can be expected. Figure   S1 depicted all these possible isomers. The computational approach was used to study at the above-mentioned level of theory for all these isomers (named I, II, and III) and to evaluate the more energetically favorable isomer. The calculation showed that the isomer (II) was the most stable isomer among all three possible isomers and therefore it was further used for adsorption study on the surface of metallofullerenes. 

Given that the metal part of metallofullerene is the most electroactive place of adsorbent towards interaction with molecules, [34] [35] [36] for each metallofullerene, the Favipiravir molecule was places near to the metal part through the two star-shown positions in Figure 2 . After making the initial geometries of Favipiravir-metallofullerene complex, they were allowed to J o u r n a l P r e -p r o o f be fully optimized first through 6-31G/B3LYP and then via 6-31+G(d,p)/ωb97xd methods, both in the water as the solvent. For each Favipiravir-metallofullerene complex, two relaxed structures were achieved (P1=position 1, and P2=position 2) depending on their initial geometries. The results revealed that for Favipiravir adsorption on C 19 M (M=Ti, Cr, Fe, and Ni), position 1 (P1) was more energetically favorable geometry than P2. The reverse result was achieved for C 19 Zn in which the P2 was more energetically favorable than P1. The superior geometry of each complex was given in Figure 3 that were selected for further investigation, while the inferior energetically favorable geometry of each complex were shown in Figure S2 .

As shown in Figure 3 , for all C 19 while there is only the possibility of one bond formation at P2 (See Figure 3 and Figure S2 ).

For the C19Zn complex, both geometries of P1 and P2 provided only one bond formation, and the superior geometry of P2 than P1 may attribute to the stronger orbital hybridizing of P2 .

The values of calculated bonds length suggest that the connection of Favipiravir molecule with all the stated metallofullerenes is considerable. It also can be found that for each metallofullerene, the Favipiravir molecule had the unique orientation and configuration that was a result of the different orbital hybridizing between them (vide infra).

J o u r n a l P r e -p r o o f which means that depending on which metallofullerene synthesis is more economical, it can be considered for Favipiravir adsorption without substantial reductions in its adsorption energy. One can find that the Favipiravir adsorption on each of the stated metallofullerenes is neither too weak nor too strong. So, it can be expected that the rate of drug release in our system is a time-dependent process and it can be expected that longer times will lead to more drug release in the target site. Fullerenes, including C 20 , a wide range of C-C vibrational frequencies appeared, which is due to the different kinds of C-C bonds. 48 These vibrations were reported in the range of 500 to 1500 cm -1 . [48] [49] [50] Therefore, the vibration peaks in this range ( Figure 5) were all related to different C-C vibrational frequencies. It should be noted that the C 20 fullerene has a symmetrical structure and if one of its atoms is replaced by a metal, the symmetry structure will be disturbed. Therefore, it can be expected that the number of vibration peaks for J o u r n a l P r e -p r o o f metallofullerene is much higher than those for pure fullerene. 50 As expected, the location of each vibration for a metallofullerene differs compared to the other, because of the presence of different metal atoms (Ti-Zn) in the structure of the C 19 M had different effects on the C-C vibrational frequencies .

Literature review revealed that for Ti-C, Cr-C, Fe-C, Ni-C, and Zn-C bonds the vibration frequency are experimentally found around 580 cm -1 , 51 484 cm -1 , 52 496 cm -1 , 53 400 ±5 cm -1 , 54 and 470 cm -1 , 55 respectively. According to Figure 5 

Given that the orbital hybridizing corresponds to the bond formation of metallofullerene and Favipiravir molecule, the frontier molecular orbitals (FMO) were analyzed for pure metallofullerenes and their equivalent complexes at the superior position (vide supra). Figure   8 represents the HOMO and LUMO of the stated metallofullerenes before and after complexation with the drug molecule. was more pronounced for the middle transition metals of the periodic table, namely chromium, iron, and nickel, but in the case of zinc metal, it was the lowest. Regarding the distribution of LUMO orbitals, it appeared to be less affected by the doped metal atom, but it was quite clear that the LUMO density on the zinc atom was as low as the HOMO density on it, which may explain why C 19 Zn was less reactive than other metallofullerenes. Table S1 . The calculated energy values of HOMO and LUMO, were -6.18 and-0.75 eV for C 19 Ti, and -6.12 and -1.18 eV for C 19 Ti-F complex, -6.69 and -0.94 eV for C 19 Cr , and -6.19 and -0.98 eV for C 19 Cr-F complex, and -6.74 and -0.86 eV for C 19 Fe, and -6.55 and -0.87 eV for C 19 Fe-F complex, and -6.71 and -1.49 eV for C 19 Ni, and -6.39 and -1.02 eV for C 19 Ni-F , and finally -7.65 and -1.02 eV for C 19 Zn and -7.61 and -1.01 for C 19 Zn-F complex. It can be concluded from Figure 9 and Table S1 that due to the Favipiravir drug adsorption, the change in the electronic structure of each metallofullerene was different, and as a result, the difference in energy levels of HOMO and LUMO were different for one system than the other. Looking at the energy changes of HOMO and LUMO, it can be seen that in all cases, by Favipiravir drug adsorption, the HOMO level shifted to less negative (or more positive) values, but the LUMO level in some systems such as C 19 Ti, C 19 Cr, and C 19 Fe shifted to the more negative values but for some systems, such as C 19 Ni and C19Zn, shifted to less negative values. These differences in HOMO and LUMO energy levels caused different changes in E g and E FL as presented in Figure 9 . Moreover, the density of states (DOS) of each system before and after drug adsorption can be found in Figures S2, S3, S4 

The algebraic sum of the electric charges of the atoms for an unreacted drug molecule is zero ( Figure 2) . However, the algebraic sum of the electric charge of the atoms of the absorbed drug molecule (Figure 10) , was no longer zero, which indicates the movement of the electric charge between adsorbent and drug molecule. The algebraic sum of the electric charge of the atoms of the adsorbed drug molecule for the studied systems was +0.359, +0.310, +0.266, and +0.329 e, upon adsorption on C 19 Ti, C 19 Cr, C 19 Fe, C 19 Ni, and C 19 Zn, respectively ( Table   2 Figure 10 , the specific electric charge of all atoms of each metallofullerene changed due to adsorption. The major change attributes to the transition metals. Figure 10 and 

The time-dependent functional theory (TD-DFT) 64 was used to calculate the UV-vis spectra and features such as the electronic transitions, the excitation energy, the absorbances, and the oscillator strength of water solvent optimized structures through TD-ωb97xd/6-31++G(d,p) method. The absorption spectra for the studied metallofullerenes were observed due to transitions from in the range of 400-600 nm (see Figure 11 ) in which this area of wavelengths may be attributed to the transition from π-π * and/or nπ *. 65 Table 3 lists the main molecular characteristics of UV-vis parameters including maximum wavelength (λ max ), excitation energy (E e ), oscillator strength (f), and major contributions of all studied systems.

According to Figure 11 and J o u r n a l P r e -p r o o f The results of the UV-vis study showed that the absorption spectra for the studied metallofullerenes were due to transitions from in the range of 400-600 nm that may be attributed to the transition from π-π * and/or nπ *. The results confirmed that metallofullerenes showed promising properties to be used as a carrier of Favipiravir drug. But the type of metal element is the critical point. The doping of fullerene with the middle elements of the first row of the periodic table, namely chromium, iron, and nickel, would be the best structure to adsorb Favipiravir, as a potential drug COVID-19 treatment.

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The authors gratefully acknowledge use of the resources of the Alabama Water Institute and the Department of Chemical and Biological Engineering at The University of Alabama.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.J o u r n a l P r e -p r o o f