key: cord-0995966-xd2chrdi
authors: Yao, Chunchun; Xiang, Feng; Xu, Zhangyi
title: Metal oxide nanocage as drug delivery systems for Favipiravir, as an effective drug for the treatment of COVID-19: a computational study
date: 2022-02-18
journal: J Mol Model
DOI: 10.1007/s00894-022-05054-6
sha: bd245518ddd4894fd165b68f71de093e4269baae
doc_id: 995966
cord_uid: xd2chrdi

This paper is a summary of research that looks at the potential of fullerene-like (MO)(12) nanoclusters (NCs) in drug-carrying systems using density functional theory. Favipiravir/Zn(12)O(12) (− 34.80 kcal/mol), Favipiravir/Mg(12)O(12) (− 34.98 kcal/mol), and Favipiravir/Be(12)O(12) (− 30.22 kcal/mol) were rated in order of drug adsorption degrees. As a result, Favipiravir attachment to (MgO)(12) and (ZnO)(12) might be simple, increasing Favipiravir loading efficiency. In addition, the quantum theory of atoms in molecules (QTAIM) assessment was utilized to look at the interactions between molecules. The FMO, ESP, NBO, and E(ads) reactivity patterns were shown to be in excellent agreement with the QTAIM data. The electrostatic properties of the system with the biggest positive charge on the M atom and the largest E(ads) were shown to be the best. This system was shown to be the best attraction site for nucleophilic agents. The findings show that (MgO)(12) and (ZnO)(12) have great carrier potential and may be used in medication delivery.

COVID-19, a new coronavirus, has spread practically everywhere on the globe since late 2019, generating a plethora of serious public health problems [1] . Due to the lack of an antiviral medication that has been authorized, many efforts have been undertaken to investigate pharmaceutical substances for the supportive therapy of the illness [2] . It is critical to look at current drugs as well as novel compounds to determine whether there's a method to treat COVID-19 swiftly. The structure of COVID-19's protease was first discovered in early 2020 [3] , spurring a substantial investigation into the efficacy of current, comparable medications on enzymatic activity [4] . In addition, identifying the mechanism of action of the ligand-target complex is crucial for moving further in the phases of drug development and design [5] [6] [7] [8] . Favipiravir has recently been investigated as a potential COVID-19 therapy, and it has been indicated as a viable option. The development of efficient medicine delivery systems has received a lot of attention recently. As a consequence, nanomaterials are now often utilized to characterize novel drug delivery (DD) methods [5] [6] [7] [8] [9] . DD materials include zero-dimensional nanoclusters (NCs), onedimensional nanotubes, and two-dimensional nanosheets [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] . Theoretical investigations have been undertaken on fullerene-like (AB) 12 (A = Mg, Al, B… and B = N, P, O…) NCs as more stable cages than other types of (AB) x structures such as nanosheets and nanotubes [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] .

Th-symmetrical metal oxide NCs, such as (MgO) 12 , (BeO) 12 , and (ZnO) 12 , have also gotten a lot of interest because of their unique features.

Previous studies have demonstrated that (BeO) 12 is thermally stable, suggesting that it might be synthesized in this manner [41] . Haertelt and coworkers [42] used density functional theory (DFT) and IR spectroscopy to demonstrate the (MgO) 12 NCs' stability. In contrast to (BeO) 12 and (MgO) 12 NCs, (ZnO) 12 NCs have been extensively investigated for their prominent roles in biomedical, gas detector, optoelectronics applications, and as a catalyst [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] . Furthermore, (ZnO) x nanocages have proven outstanding efficacy in DD applications due to their improved biocompatibility and reduced cost. The Zn 12 O 12 NC was successfully synthesized [55] , and its many uses were investigated [56, 57] . Regardless, few research assessing the efficacy of such NCs in DD systems have been conducted. As a consequence, the present study focuses on adsorbing pharmaceuticals on Zn 12 O 12 , Mg 12 O 12 , and Be 12 O 12 NCs, which have been identified as the optimal clusters for DD systems. The interactions of (MO) 12 NCs and Favipiravir were investigated using DFT. The primary goal of this research is to conduct a theoretical investigation of (MO) 12 /Favipiravir systems to determine if Favipiravir-controlled administration is feasible. The density of state (DOS), adsorption energy, molecule electrostatic potential, UV-vis spectrum, and electronic characteristics were all found as a result of this research. The atoms' quantum theory of molecules (QTAIM) findings was also used to identify the interactions in terms of nature.

The current study used DFT calculations to better achieve Favipiravir energetic assessments and geometrical relaxation on (MO) 12 complexes. This work used the generalized gradient approximation, Perdew-Burke-Ernzerhof (PBE) one, for exchange-correlation energy functional and Grimme dispersion corrected PBE using Gaussian 09 to optimize the geometry and determine the electrical characteristics. Double numerical basis sets, such as polarization functions, have been used to illustrate atomic valent orbitals [58] [59] [60] [61] . To get Favipiravir adsorption energy, the energy difference between the solitary NC-Favipiravir assembly and Favipiravir/NC complexes was discovered.

In order to determine if the expected (MO) 12 NCs could be experimentally manufactured, the cohesive energy E coh was computed as follows:

where E tot denotes the overall energy of the NCs is, Ei represents the atomic energy, ni is the number of type-i atoms (i = Zn, O, Be, and Mg) and j is the number of the total atoms of (MO) 12 . It was necessary to quantify the energy gap (E g ) of the lowest and highest occupied molecular orbitals in order to assess Favipiravir adsorption contributions to NC electrical characteristics (LUMO and HOMO). Natural bond orbital (NBO) analysis of charge was used to assess charge transfer between drug molecules and NCs [62] . AIMALL was also used to create QTAIM and better understand the complexes' interactions [63] .

The intact (MO) 12 and optimized Favipiravir structures are shown in Fig. 1 . As can be observed, the intact NCs have six tetragons and eight hexagons with symmetry of Th. (MgO) 12 , (BeO) 12 , and (ZnO) 12 have the angles of a hexagon (tetragon) of 114.2 (86.6), 111.8 (80.8), and 108.6 (86.9) degrees, respectively. Two forms of M-O bonds exist in the NCs: a hexagonal double bond (d1) as well as bonds shared by a hexagon and a tetragon (d2). The bond sizes of d1 (d2) of (BeO) 12 , (MgO) 12 , and (ZnO) 12 , respectively, are 1.54(1.60), 1.88(1.95), and 1.89(1.99) Å. The current study used the calculations of harmonic vibrational frequency at the level of the theory of PBE/6-31 + g(d) to guarantee that the structures corresponded to energy minima. On the surface of potential energy, the structures were discovered to be real stationary points. (BeO) 12 , (MgO) 12 , and (ZnO) 12 have harmonic frequencies of 200.6-1194.1 cm −1 , 100.6-764.2 cm −1 , and 74.8-650.2 cm −1 , respectively. The results are consistent with those of Li and coworkers [64] , who investigated NC acetone sensitivity. The NC electrostatic potential (ESP) graphs are shown in Fig. 2 , with the red negative regions representing relative charge buildup and the blue positive regions representing charge depletion.

Based on Fig. 2 , the best attraction locations for nucleophilic agents are Be, Mg, and Zn atoms.

The top perspective for intact NCs' frontier molecular orbital (FMO) is also shown in Fig. 2 . As can be observed, the NC HOMOs were discovered to have a preferential distribution on O atoms.

As a consequence of the FMO findings, the optimum nucleophilic agent attraction regions of the Be, Mg, and Zn atoms were discovered.

The NCs were evaluated using the NBO method. The atomic charges of NBO on the Be, Mg, and Zn atoms were shown to be + 1.16, + 1.16, and + 1.32 e, respectively, indicating a considerable charge transfer from the mentioned atoms to the O atom. E coh was also computed using Eq. (1), proving that the expected nanoclusters could be manufactured experimentally. For Be 12 O 12 , Zn 12 O 12 , and Mg 12 O 12 , E coh was determined to be − 7.25, − 5.55, and − 5.76 eV, respectively. According to the findings, (BeO) 12 has a lower E coh than (MgO) 12 and (ZnO) 12 , implying that (BeO) 12 might be simpler to produce than (MgO) 12 and (ZnO) 12 . For (BeO) 12 , (MgO) 12 , and (ZnO) 12 , E g was shown to be 7.23, 3.85, and 2.13 eV, respectively. The E g findings were inconsistent with previous research [64] . The DOS findings are shown in Fig. 3 so that the influence of the M atom on the NC electronic characteristics can be checked. Large differences emerged towards the Fermi level, as can be shown, due to significant interactions of M-O on both sides. In addition, the valence level for (ZnO) 12 increases in energy as the Fig. 2 The analysis of ESP and the LUMO and HOMO of the intact (MO) 12 NCs conduction level decreases. E g is significantly reduced as a result of this. As a result, (ZnO) 12 (E g = 2.13 eV) may be classified as a semiconductor nanoparticle, while (BeO) 12 (E g = 7.23 eV) and (MgO) 12 (E g = 3.85 eV) are often metal oxides that have been insulated.

The current study looked at a range of configurations to find the most stable adsorption on the NC surface, such as placing Favipiravir oxygen, nitrogen, and fluorine atoms at various positions, such as the tops of Mg, Zn, O, and Be atoms, as well as the tetragonal and hexagonal ring centers. E ads , the shortest NC-drug distance, and the most stable electronic configurations are shown in Fig. 4 . Based on Fig. 4 , the optimized-geometry Favipiravir has the maximum propensity for O and M atom interaction. This is in line with the ESP and FMO findings. The interaction distances of the Favipiravir/Be 12 O 12 , Favipiravir/Zn 12 O 12 , and Favipiravir/Mg 12 O 12 complexes are also shown in Fig. 4 . As can be observed, the interaction distances between Favipiravir/Zn 12 O 12 and Favipiravir/Mg 12 O 12 are quite short. As a consequence, it is safe to assume that chemisorption will take place.

The adsorption energies of (BeO) 12 , (ZnO) 12 , and (MgO) 12 were shown to interact with Favipiravir The current study looked at the influence of a solvent on Favipiravir adsorption onto NCs in aqueous conditions. The polarizable continuum model was used to quantify the influence of water as the solvent (ε = 78.4). According to the results of E ads , the complexes were compared in aqueous and gaseous phases ( Table 1) . As can be observed, the energy levels in both phases are fully negative, indicating that the complexes are stable. The greater the possible solubility of the NC to affect the Favipiravir-NC interaction, the larger the absolute amount of negative adsorption energy in the aqueous phase. The DOS data are shown in Fig. 5 to validate the impacts of Favipiravir on NC electronic characteristics. As shown in Fig. 6 , (MgO) 12 and (ZnO) 12 displayed minor post-Favipiravir adsorption modifications in LUMO and HOMO. As a result, E g stayed almost unaltered. The valence (conduction) level of Favipiravir/(BeO) 12 , on the other hand, rose (reduced). As a consequence, the E g of (BeO) 12 was smaller than that of its immaculate equivalent.

At the level of the theory of PBE/6-31 + g(d), the UV-Vis spectrum of both pure NCs and Favipiravir-nanocluster complexes were measured. Table 2 lists the important transitions (i.e., the greatest oscillator strengths (f)). Based on Table 2 , the greatest adsorption wavelengths of the intact (BeO) 12 , (ZnO) 12 , and (MgO) 12 were determined to be 294.72, 372.36, and 411.45 nm, respectively. The greatest oscillator strengths were 0.1241, 0.0032, and 0.0035, respectively. The majority of adsorption wavelength peaks are explained by HOMO → LUMO transitions. The intact NC adsorption bands dropped to higher wavelengths when Favipiravir was adsorbed onto them. Thus, it is possible to deduce that the electronic spectrum of the complexes experiences a redshift to higher wavelengths. The most significant redshift was seen in Favipiravir/(BeO) 12 (126 nm).

AIM is a capable tool for determining the interactions between molecules. AIM can identify the bond critical points (BCPs) between interactive systems using topological variables. The improved Favipiravir/NC complexes are shown as molecular graphs in Fig. 6 . Based on Table 2 , at Based on Table 2 , the Favipiravir/(MgO) 12 and Favipiravir/(ZnO) 12 

The Favipiravir drugs' adsorption onto fullerene-like (MO) 12 NCs was investigated in this work. A study of the NC's adsorption energies revealed that (MgO) 12 look at the interactions between molecules. The Eads, FMO, NBO, and ESP reactivity patterns were shown to be in excellent agreement with the QTAIM data. The electrostatic properties of the system with the biggest positive charge on the M atom and the largest Eads were shown to be the best. This system was shown to be the best attraction site for nucleophilic agents. The findings show that (MgO) 12 and (ZnO) 12 have great carrier potential and may be used in medication delivery. However, more in vivo research is needed to confirm these findings.

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