A Proposed Insight into the Anti-viral Potential of Silver Nanoparticles against Novel Coronavirus Disease (COVID-19)

Stavropol State Medical University, Stavropol, Russia. 2 North Ossetian State Medical Academy, Vladikavkaz, Republic of North Ossetia, Russia. I.M. Sechenov First Moscow State Medical University, Moscow, Russia. 4 Dagestan State Medical University, Makhachkala, Dagestan, Russia. Chechen State University Medicine Institute, Russia. Stavropol Regional Clinical Consulting and Diagnostic Center, Stavropol, Russia. 7 Stavropol Regional Clinical Hospital, Stavropol, Russia. North Caucasus Federal University, Stavropol, Russia.


INTRODUCTION
The study of the biological properties of metal nanoparticles, associated with the intensive development of nanomedicine and nanopharmacology, is one of the priority modern directions [1][2][3][4][5][6][7][8]. Nanomedicine studies the possibility of using nanotechnologies in medical practice for the prevention, diagnosis and treatment of various diseases [9,10]. Of particular interest in this regard is the development and study of the mechanisms of action of drugs based on silver nanoparticles [11][12][13]. It should be noted that silver preparations, such as collargol and protargol, have been widely used for a long time as antiseptic and antiinflammatory agents [14,15]. With the advent of nanotechnologies, new opportunities have appeared in terms of developing more effective drugs using silver nanoparticles [16,17]. It has been established that silver in the nanoscale range has a more pronounced bactericidal, antiviral, antifungal and antiseptic effect and serves as a highly effective antibacterial agent against a wide range of pathogenic microorganisms [18,19]. Due to the larger specific surface area of nanoparticles, the areas of contact of nanosilver with bacteria or viruses increase, which significantly increases its bactericidal properties [20,21]. Accordingly, the use of silver in the form of nanoparticles makes it possible to reduce the concentration of the metal hundreds of times while preserving all its bactericidal properties. Intensive studies of recent years have shown the anti-inflammatory effects of silver nanoparticles [22,23]. However, the possibilities of using silver nanoparticles require further detailed research due to their insufficiently studied effect on various tissues and body systems.
At the moment, the study of the prospects for the use of silver nanoparticles in the treatment of inflammatory processes, the study of possible toxicological effects and the pathogenetic justification of optimal approaches to the use of silver nanoparticles are relevant and require further in-depth study. Another promising direction of studying silver nanoparticles is the assessment of antiviral activity in relation to COVID-19 coronavirus infection [24,25].
A detailed analysis of the morphology of the coronavirus, its microstructural structure and RNA allows us to conclude that the most effective means in the fight against coronavirus can be the use of nanoscale silver particles exhibiting acute bactericidal (Fig. 2) and antiviral activity [27].
The mechanism of the toxic effect of nanosilver on bacterial cells and viruses is possible in several ways: interaction and damages to cell membranes, cellular uptake, reactive oxygen species (ROS) production, interaction with and damage to cellular proteins, binding and damages to cellular DNA and RNA repair [28]. In the case of coronavirus, there are 3 possible directions of nanosilver exposure: membrane destruction, RNA destruction and spike protein damage [29]. The effectiveness of each type of toxic effect of nanosilver on coronavirus has yet to be determined in the course of numerous experiments, the basis for which will be models of the mechanism of action. The purpose of this work was to conduct computer quantum-chemical modeling of the mechanism of the effect of nanoscale silver particles on the morphology and micro-, nanostructure of the coronavirus.

MATERIALS AND METHODS
Computer quantum-chemical modeling of the process of silver nanoparticles effect on coronavirus was performed in the QChem program using the IQmol molecular editor. The calculation was performed on the equipment of the Data Processing Center (Schneider Electric) of the North Caucasus Federal University. Calculation characteristics: Energy, metod -B3LYP; basis -3-21G, convergence-5, force field-Ghemic [30,31].
We used the QChem program using the IQmol molecular editor, the description of the work is described below: Since nanosilver can be very active with amino acids, it was suggested that the main target of nanosilver will be spike protein (Fig. 4). The model of the effect of nanosilver on coronavirus presented in Fig. 4 is taken as the main one in this paper.

RESULTS AND DISCUSSION
At the first stage of research, quantum-chemical modeling of coronavirus's spike protein amino acids and nanosilver interaction was performed.
The obtained models of spike protein amino acids with nanosilver, electron density distributions, electron density distribution gradients, and molecular orbitals for each amino acid are shown in Figs. 5-17.
Silver nanoparticles can interact with proline, which is due to the presence of an additional amino group in the proline structure. The carboxyl and amino groups in the serine structure participate in the formation of a peptide bond, so they do not participate in interaction with silver nanoparticles. The addition of silver nanoparticles to the hydroxyl group has a low probability, so the formation of the "serinenanosilver" complex is improbable.
The carboxyl and amino groups in the threonine structure participate in the formation of a peptide bond, so they do not participate in interaction with silver nanoparticles. The formation of the "threonine-nanosilver" complex is improbable, due to the absence of additional amino and carboxyl groups in the threonine structure. The addition of silver nanoparticles to the hydroxy group has a low probability.
Silver nanoparticles can interact with cysteine, which is due to the presence of the SH group in the cysteine structure. The formation of the "tyrosine-nanosilver" complex is unlikely, due to the absence of additional amino and carboxyl groups in the tyrosine structure. The addition of silver nanoparticles to the hydroxy group has a low probability.

Fig. 10. Model of "aspartic acid-nanosilver" molecular complex (A), electron density distribution (B), highest occupied molecular orbital HOMO (C), lowest unoccupied molecular orbital LUMO (D) and electron density distribution gradient (E)
The formation of the complex "aspartic acidnanosilver" has a high probability, which is due to the presence of an additional carboxyl group in the structure of aspartic acid.
The formation of the "tryptophan-nanosilver" complex has a high probability, which is due to the presence of an additional NH group in the tryptophan structure.

. Model of "glutamic acid-nanosilver" molecular complex (A), electron density distribution (B), highest occupied molecular orbital HOMO (C), lowest unoccupied molecular orbital LUMO (D) and electron density distribution gradient (E)
The formation of the complex "glutamic acidnanosilver" has a high probability, due to the presence of an additional carboxyl group in the structure of glutamic acid.
The formation of the "histidine-nanosilver" complex has a high probability, which is due to the presence of an additional NH group in the histidine structure.

. Model of "asparagine-nanosilver" molecular complex (A), electron density distribution (B), highest occupied molecular orbital HOMO (C), lowest unoccupied molecular orbital LUMO (D) and electron density distribution gradient (E)
Silver nanoparticles can interact with asparagine, which is due to the presence of an additional amino group in the structure of asparagine.
The formation of the "arginine-nanosilver" complex has a high probability, which is due to the presence of an additional amino group in the arginine structure.

. Model of "lysine-nanosilver" molecular complex (A), electron density distribution (B), highest occupied molecular orbital HOMO (C), lowest unoccupied molecular orbital LUMO (D) and electron density distribution gradient (E)
The formation of the "lysine-nanosilver" complex has a high probability, which is due to the presence of an additional amino group in the histidine structure.
The formation of the "glutamine-nanosilver" complex has a high probability, which is due to the presence of an additional amino group in the glutamine structure.
As a result of quantum chemical modeling, it was found that silver nanoparticles can interact with the following amino acids: Proline, glutamine, lysine, arginine, asparagine, histidine, glutamic and aspartic acids, tryptophan and cysteine, which is due to the presence of additional -NH2, -NH, -SH and -COOH groups in these amino acids that are not involved in the formation of a peptide bond. These free additional groups make possible interaction with nanosilver. Thus, the interaction of silver nanoparticles with threonine, serine, and tyrosine is unlikely. Obtained data are confirmed by the results of quantum chemical calculations (Table 1).   Table 1 shows a decrease in the system when adding nanosilver. I.e., the interaction of nanosilver with amino acids is an energetically beneficial process. The most energy-efficient interaction is the formation of the "tryptophannanosilver" complex (E= -5856.83 kkal/mol), but the difference in the energy of interaction of nanosilver with other amino acids is not very significant. According to the results of quantum chemical calculations, the most stable complex is the "cysteine-Ag nanoparticles" (ΔE = 0.16 a. u.).
Molecular docking could be done to further strengthen the claim that the silver nanoparticle can be a potential anti-COVID drug.
Checking the individual interaction between the nanosilver and the specific amino acids is a good result to provide insight about the silver nanoparticles, but the specific structure of the proteins in coronavirus could affect the system during inhibition. With this we suggest conducting molecular dynamics between the nanosilver and the proteins involved in the coronavirus.

CONCLUSION
As a result of quantum chemical modeling, it was found that silver nanoparticles can interact with the following amino acids: Proline, glutamine, lysine, arginine, asparagine, histidine, glutamic and aspartic acids, tryptophan and cysteine, which is due to the presence of additional -NH2, -NH, -SH and -COOH groups in these amino acids that are not involved in the formation of a peptide bond. The freedom of additional groups makes it possible to interact with nanosilver. Analysis of the obtained data showed that the most energy-efficient interaction is the formation of the "tryptophan-nanosilver" complex (E= -5856.83 kkal/mol). According to the results of quantum chemical calculations, the most stable complex is the "cysteine-nanosilver" (ΔE = 0.16 a. u.).

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.
"Biorithm-E" in the complex treatment of odontogenic inflammatory diseases of the maxillofacial region.