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IMR Press / FBL / Volume 27 / Issue 5 / DOI: 10.31083/j.fbl2705152
Open Access Original Research
Simple Theoretical Criterion for Selection of Natural Compounds with Anti-COVID-19 Activity
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1 Biomed Protection, Galveston, TX 77550, USA
2 Laboratory for Bioinformatics and Computational Chemistry, Institute of Nuclear Sciences Vinca, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia
3 Department of Pathology, Galveston National Laboratory, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77550, USA
*Correspondence: veljko@biomedprotection.com (Veljko Veljkovic)
Front. Biosci. (Landmark Ed) 2022 , 27(5), 152; https://doi.org/10.31083/j.fbl2705152
Submitted: 31 March 2022 | Revised: 6 April 2022 | Accepted: 12 April 2022 | Published: 11 May 2022
This is an open access article under the CC BY 4.0 license.
Abstract

Background: A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the leading threat to global health. An effective antiviral could not only help those still vulnerable to the virus but could be a critical treatment if a virus emerges toward evading coronavirus disease 2019 (COVID-19) vaccines. Despite the significant efforts to test already-approved drugs for their potential to kill the virus, researchers found very few actually worked. Methods: The present report uses the electronic molecular descriptors, the quasi-valence number (AQVN), and the electron-ion interaction potential (EIIP), for the analysis of natural compounds with proven therapeutic activity against the COVID-19. Results: Based on the analysis of the electronic properties of natural compounds which are effective against SARS-CoV-2 virus the simple theoretical criterion for the selection of candidate compounds for the treatment of COVID-19 is proposed. Conclusions: The proposed theoretical criterion can be used for the identification and optimization of new lead compounds for the treatment of the COVID-19 disease and for the selection of the food and food supplements which could have a beneficial effect on COVID-19 patients.

Keywords
natural compounds
secondary metabolites
flavonoids
coronavirus
COVID-19
electron-ion interaction potential
average quasi-valence number
1. Introduction

The outbreak of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to coronavirus disease-19 (COVID-19); a pandemic disease that represents the global health, social and economic threat. Currently, SARS-CoV-2 is spreading worldwide very rapidly and its control is very difficult because there is no available effective vaccine or drugs. As of October, 2021 globally, more than 247 million people have been diagnosed with COVID-19, 223 countries have been affected and more than 5 million deaths have been reported. Therefore, it is an urgent need for development of effective drugs for treatments of the COVID-19 disease.

Natural products have been the primary source of medicines in all cultures with a vast diversity of terrestrial and marine organisms; also, they are the most successful source of drug leads for the treatment of many diseases [1]. Flavonoids are extensively distributed natural products produced by plants having an essential role in plant physiology, with a potential anti-inflammatory, anticancer, antibacterial, antifungal, and antiviral activity [2].

Around ten years of research is needed for the development of de-novo medicines. Thus, the repurposing of natural products could be an efficient strategy against SARS-CoV-2 infection [3].

Some natural compounds have been shown to possess antiviral activities against various viruses (influenza virus, human immunodeficiency virus (HIV), hepatitis C and B viruses, measles-virus, herpes simplex virus, poliovirus and human coronaviruses SARS and MERS) [4, 5, 6, 7, 8, 9, 10, 11]. The potential treatments for viral diseases using natural plant compounds are actively studied worldwide, especially against viruses from the coronavirus group were intensified last year. Furthermore, in recent years, understanding the antiviral mechanisms of complex plant extract and isolated plant-derived compounds have been actively studied. In addition to molecular docking studies, in silico analyses of extracted compounds were used in these studies [12]. To date, numerous Chinese herbs and herbal formulations have been reported to possess antiviral activities [13, 14, 15]. This suggests the natural phyto compounds and medicinal plant-based formulations as a base for the development of novel drugs for the treatment of the COVID-19 disease.

Previously, it was showed that the biological properties of organic molecules are determined by the physical parameters the electron-ion interaction potential (EIIP) and the average quasy-valence number (AQVN) [16]. These electronic molecular descriptors served as a base for the in silico screening of different molecular libraries for candidate drugs against HIV, influenza virus, Ebola virus, Leishmania disease, malaria disease and antibiotic-resistant bacteria [17, 18, 19, 20, 21, 22, 23]. The purpose of this study is to develop the criterion for in silico selection of natural compounds that have promising antiviral effects against SARS-CoV-2 virus.

2. Materials and Methods

It has been previously proposed the model of the molecular interactions in biological systems which encompass two steps [16, 24]. The first step is determined by the selective long-range forces which allow specific recognition and targeting between interacting molecules at a distance longer than one linear dimension of the interacting macromolecules (102–103 Å). These forces directly influence the number of productive collisions between interacting molecules. The second step is the chemical binding between interacting molecules which involves the weak non-covalent forces (van der Waals, hydrogen bonding, ionic interactions, etc.) which operate over a short distance range ($<$5 Å).

The number of valence electrons and the electron–ion interaction potential (EIIP), are the molecular descriptors which determine the long-range properties of biological molecules [16]. These physical parameters are derived from the general model pseudopotential [25, 26] and for organic molecules are determined by the following equations.

(1)$\mathrm{W}=0.25\mathrm{Z}\text{*}\sin\left(1.04\pi\ \mathrm{Z}\text{*}\right)/2\pi$

where Z* is the AQVN determined by

(2)$\mathrm{Z}\text{*}=\sum\nolimits_{m}\mathrm{}\mathrm{n}_{\mathrm{i}}\mathrm{Z}% _{\mathrm{i}}/\mathrm{N}$

where Z${}_{i}$ is the valence number of the i-th atomic component, n${}_{i}$ is the number of atoms of the i-th component, m is the number of atomic components in the molecule and N is the total number of atoms. The EIIP values calculated according to Eqns. 1 and 2 are in Rydbergs (Ry = 13.5eV).

We will further use these molecular descriptors for analysis of natural compounds with the anti-COVID-19 activity.

3. Results

Several laboratory and clinical studies have demonstrated remarkable efficacy of different herbal preparations in prevention and treatment of the COVID-19 disease [27, 28, 29, 30, 31]. This especially concerns the traditional Chinese medicine (TCM) which successfully used for clinical treatment of mild, moderate, severe and critical cases and convalescence [32]. However, these studies still leave the question of whether these extraordinary health effects are the consequence of some unique properties of the herbal ingredients in these preparations. In order to answer this question, we analyzed the electronic properties, represented by the molecular descriptors AQVN and EIIP, of chemical ingredients of 22 therapeutic TMC preparations recommended for COVID-19 in China [33]. The molecular descriptors AQVN and EIIP, calculated for 92 essential compounds from these preparations, are given in Table 1 (Ref. [30]) and Fig. 1 (Ref. [30]).

Fig. 1.

The distribution of electron donors (n${}^{+}$) and electron-acceptors (n${}^{-}$) in TMC [30].

Table 1.The AQVN and EIIP parameters of the essential chemical ingredients of the therapeutic TMC preparations recommended for COVID-19 in China [30].
 Compound Formula AQVN EIIP [Ry] kaempferol C15H10O6 3.419 0.1339 quercetin C15H10O7 3.500 0.1260 luteolin C15H10O6 3.419 0.1339 glycyrrhetinic acid C30H46O4 2.375 0.0941 indigo C16H10N2O2 3.200 0.1092 $\beta$-sitosterol C29H50O 2.150 0.0578 naringenin C15H12O5 3.188 0.1060 isorhamnetin C16H12O7 3.371 0.1341 formononetin C16H12O4 3.125 0.0879 isoflavone C15H10O2 3.037 0.0577 licochalcone B C16H14O5 3.086 0.0750 glyasperin C C21H24O5 2.760 0.0435 licochalcone a C21H22O4 2.766 0.0416 3-methoxyglabridin C21H22O5 2.833 0.0188 anhydroicaritin C21H20O6 2.979 0.0359 stigmasterol C29H48O 2.180 0.0644 6-(3-oxoindolin-2-ylidene) indolo (21-b) C23H13N3O2 3.220 0.1138 quinazolin-12-one C14H8N2O2 3.308 0.1293 bicuculline C20H17NO6 3.136 0.0915 physciondiglucoside C28H32O15 3.120 0.0863 dihydroverticillatine C27H41N02 2.271 0.0820 licoisoflavanone C20H18O6 3.046 0.0608 574’-trihydroxy-8-methoxyflavone C16H12O6 3.294 0.1275 acacetin C16H12O5 3.212 0.1121 irisolidone C17H14O6 3.189 0.1064 wogonin C15H10O5 3.333 0.1319 baicalein C15H10O5 3.333 0.1319 glycyrrhizic acid C42H62O16 2.717 0.0564 hesperidin C28H34O15 3.065 0.0678 hyperoside C21H20O12 3.321 0.1308 andrographolide C20H30O5 2.546 0.0906 gallic acid C7H6O5 3.556 0.1150 rosmarinic acid C18H16O8 3.238 0.1179 rutin C27H30O16 3.206 0.1105 chlorogenic acid C16H18O9 3.163 0.0993 tanshinone II A C19H18O3 2.800 0.0304 hydroxysafflor yellow A C27H32O16 3.147 0.0946 paeoniflorin C23H28O11 3.000 0.0439 chlorogenin C27H44O4 2.347 0.0918 5-Hydroxy-67345-pentamethoxyflavone C20H20O8 3.083 0.0742 isokaempferol C15H10O6 3.419 0.1339 morin C15H10O7 3.500 0.1260 gardenin E C19H18O9 3.217 0.1133 artemisetin C20H20O8 3.083 0.0742 genistein C15H10O5 3.333 0.1319 dryobalanone C30H50O3 2.265 0.0810 curcumin C21H20O6 2.979 0.0359 elemicin C12H16O3 2.645 0.0742 chrysoeriol C16H12O6 3.294 0.1275 apigenin C15H10O5 3.333 0.1319 scutellarin C21H18O12 3.412 0.1342 oroxylin-7-O-glucuronide C22H20O11 3.283 0.1259 forsythin C27H34O11 2.889 0.0016 forsythiaside E C20H30O12 2.935 0.0193 ursodeoxycholic acid C24H40O4 2.353 0.0923 chenodeoxycholic acid C24H40O4 2.353 0.0923 ophiopogonin D C44H70O16 2.631 0.0772 ginsenoside rg 2 C42H72O14 2.531 0.0921 methyl ophiopogonanone A C19H18O6 3.023 0.0526 ginsenoside Rb2 C56H92O25 2.694 0.0626 ginsenoside R0 C48H76O19 2.671 0.0682 ophiopogon A C44H70O18 2.682 0.0656 sanchinoside rd C48H82O18 2.581 0.0860 ophiopogonanone E C19H20O7 3.000 0.0439 schisanlactone E C30H44O4 2.410 0.0959 N-transferuloyltyramine C20H23NO5 2.816 0.0248 angeloylgomisin O C28H34O8 2.771 0.0399 gomisin-A C23H28O7 2.793 0.0327 gomisin R C22H24O7 2.906 0.0079 changnanic acid C29H44O4 2.390 0.0985 kadsulactone C30H44O3 2.364 0.0932 kadsulignan B C23H26O7 2.857 0.0102 ginsenoside rh2 C36H62O8 2.396 0.0953 bisindigotin C32H18N4O2 3.178 0.1036 irisolidone C17H14O6 3.189 0.1064 8-isopentenyl-kaempferol C20H18O6 3.046 0.0608 neobaicalein C19H18O8 3.156 0.0972 dihydrooroxylin A C16H14O5 3.086 0.0750 chrysin-5-methylether C16H12O4 3.125 0.0879 catechin C15H14O6 3.143 0.0934 72-dihydroxy-58-dime thoxyflavone C17H14O6 3.189 0.1064 7-hydroxy-58-dimethoxy-2-phenylchromone C17HH14O5 3.054 0.0639 57-dihydroxy-8-methoxy-2-(2-methoxyphenyl)chromone C17H14O7 3.263 0.1227 formononetin C16H12O4 3.125 0.0879 Isoglabrolide C30H44O4 2.410 0.0959 glabrolide C30H44O4 2.410 0.0959 ebeiedinone C27H43NO 2.250 0.0784 peimisine C27H41NO3 2.389 0.0949 verticinone C27H43NO3 2.351 0.0922 imperialine C27H43NO3 2.351 0.0922 ussuriedinone C27H35NO3 2.515 0.0935 euchrenone A5 C25H26O4 2.727 0.0534 glycyrol C21H18O6 3.067 0.0684 indirubin C16H10N2O2 3.200 0.1092 acacetin C16H12O5 3.212 0.1121 syrigin C17H24O9 2.920 0.0134 emodin C15H10O5 3.333 0.1319 7-Omethylisomucronulatol C18H20O5 2.837 0.0174 formononetin C16H12O4 3.125 0.0879 ellagic acid C14H6O8 3.929 0.0416 39-di-O-methylnissolin C17H16O5 3.000 0.0439

Recently, 105 herbs from 24 TCM prescriptions that are highlighted in the guidelines for the treatment of COVID-19, were analyzed [34]. The results of this analysis showed that the combination of Amygdalus Communis Vas (ACV) and Ephedra sinica Stapf (ESS) is the best for the treatment of patients in almost all the stages of COVID-19, so ACV and ESS (AE) were selected as the most important herbal pair [34]. The molecular descriptors AQVN and EIIP, calculated for 26 active ingredients of the herbal pair AE is given in Table 2 (Ref. [31]) and Fig. 2 (Ref. [31]).

Fig. 2.

The distribution of electron donors (n${}^{+}$) and electron-acceptors (n${}^{-}$) in the herbal preparation AE [31].

Table 2.The molecular descriptors AQVN and EIIP calculated for the active ingredients of the herbal pair AE for treatment of the COVID-19 disease [31].
 Compound Formula AQVN EIIP [Ry] Quercetin C15H10O7 3.500 0.1260 Kaempferol C15H10O6 3.419 0.1339 Luteolin C15H10O6 3.419 0.1339 $\beta$-sitosterol C29H50O 2.150 0.0578 Naringenin C15H12O5 3.188 0.1060 Stigmasterol C29H48O 2.180 0.0644 Herbacetin C15H10O7 3.500 0.1260 Genkwanin C16H12O5 3.212 0.1121 Taxifolin C15H12O7 3.352 0.1333 Pectolinarigenin C17H14O6 3.189 0.1064 (+)-catechin C15H14O6 3.143 0.0934 Diosmetin C16H12O6 3.294 0.1275 Eriodictyol C15H12O6 3.273 0.1243 Truflex OBP C20H30O4 2.482 0.0956 Leucopelargonidin C15H14O6 3.143 0.0934 Resivit C15H14O7 3.222 0.1144 (+)-Leucocyanidin C15H14O7 3.222 0.1144 Mandenol C20H36O2 2.207 0.0702 24-Ethylcholest-4-en-3-one C29H48O 2.180 0.0644 poriferast-5-en-3beta-ol C29H50O 2.150 0.0578 campest-5-en-3beta-ol C28H48O 2.156 0.0591 Stigmasterol C29H48O 2.180 0.0644 l-SPD C19H21NO4 2.800 0.0304 Estrone C18H22O2 2.534 0.0928 Glabridin C20H20O4 2.818 0.0242 Machiline C17H19NO3 2.750 0.0466 Licochalcone C21H22O4 2.766 0.0416 Phaseol C20H16O5 3.073 0.0707 (+)-catechin C15H14O6 3.143 0.0934 Glycyrol C3H8O3 2.714 0.0570 Liquiritin C21H22O9 3.077 0.0769 CLR C27H46O 2.162 0.0606 Sitosterol C29H50O 2.150 0.0578 Spinasterol C29H48O 2.180 0.0644 gondoic acid C20H38O2 2.167 0.0616 11,14-eicosadienoic acid C20H36O2 2.207 0.0702 Mairin C22H22O8 3.038 0.0582

Natural polyphenols, playing a relevant role in reducing inflammation and preventing the onset of serious chronic diseases, have been recently reviewed as promising agents to fight COVID-19 [35]. The AQVN and EIIP values calculated for 50 natural polyphenols with demonstrated anti-COVID-19 activity [35] are given in Table 3 (Ref. [32]) and Fig. 3 (Ref. [32]). The molecular descriptors AQVN and EIIP were also calculated for hypericin which is nathodyanthrone and not a typical phenolic compound [36].

Fig. 3.

The distribution of electron donors (n${}^{+}$) and electron-acceptors (n${}^{-}$) in polyphenols which are active against the COVID-19 disease [32].

Table 3.The molecular descriptors AQVN and EIIP calculated for polyphenols which are active against the COVID-19 disease [32].
 Compound Formula AQVN EIIP [Ry] Cyanidin C15H11O6 3.344 0.1327 Daidzein C15H10O4 3.241 0.1185 Dieckol C36H22O18 3.605 0.1016 Genistein C15H10O5 3.333 0.1319 Mearnsitrin C22H22O12 3.250 0.1202 Myricitrin C21H20O12 3.321 0.1307 Psoralidin C20H16O5 3.073 0.0707 Quercetin 3-O-D-glucoside C21H19O12 3.365 0.1339 Rutin C27H30O16 3.205 0.1105 Xanthoangelol E C21H22O6 2.898 0.0050 Benzoic acid C7H6O2 3.067 0.0684 Ellagic acid C14H6O8 3.929 0.0416 Gallic acid C7H6O5 3.556 0.1150 Kaempferol 3-O-rutinoside C27H30O15 3.167 0.1004 Naringenin C15H12O5 3.188 0.1060 Oleuropein C25H32O13 3.000 0.0439 Quercetin C15H10O7 3.500 0.1260 Quercetin 3-O-rutinoside C27H30O16 3.206 0.1105 Resveratrol C14H12O3 2.966 0.0308 Scutellarein C15H10O6 3.419 0.1339 Cyanidin 3-O-glucoside C21H21O11 3.226 0.1154 Epigallocatechin C22H18O11 3.373 0.1342 Epigallocatechin gallate C22H18O11 3.373 0.1342 Hypericin C30H16O8 3.407 0.1343 Kaempferol C15H10O6 3.419 0.1339 Cryptotanshinone C19H20O3 2.714 0.0570 Luteolin C15H10O6 3.419 0.1339 Afzelin C21H20O10 3.216 0.1130 Apigenin C15H10O5 3.333 0.1319 Baicalin C21H18O11 3.360 0.1337 Biorobin C27H30O15 3.167 0.1004 Caffeic acid C9H8O4 3.238 0.1179 Catechin C15H14O6 3.143 0.0934 Chlorogenic acid C16H18O9 3.163 0.0993 Chrysin C15H10O4 3.241 0.1185 Curcumin C21H20O6 2.979 0.0359 Delphinidin C15H11O7 3.424 0.1337 Ferulic acid C10H10O4 3.083 0.0742 Galangin C15H10O5 3.333 0.1319 Hesperetin C16H14O6 3.167 0.1004 Isoferulic acid C10H10O4 3.083 0.0742 Nobiletin C21H22O8 3.020 0.0513 Nympholide A C30H26O15 3.324 0.1310 Pinocembrin C15H12O4 3.100 0.0787 Rhoifolin C27H30O14 3.127 0.0885 Rutin C27H30O16 3.206 0.1105 Taiwanhomoflavone A C33H24O10 3.224 0.1148 Tangeretin C20H20O7 3.021 0.0519 Viniferin C28H22O6 3.036 0.0572 Artepillin C C19H24O3 2.565 0.0882

The previous analysis of 45,010,644 compounds randomly selected from the PubChem database [37] showed that 90.5% of these compounds have EIIP and AQVN values in the intervals (0.00–0.10 Ry) and (2.4–3.2), respectively (Fig. 4, Ref. [33]) [24]. This part of the EIIP/AQVN space, encompassing the majority of analyzed compounds, was referred as the “basic chemical space” (BCS) [24]. The small fraction (4.3%) of analyzed compounds from the PubChem, representing the strong electron donors and are located left of BCS. The compounds with the strong electron-acceptor properties (5.3% of analyzed compounds from the PubChem) are in the domain right of BCS. Results presented in Table 4 show that the percentage of strong electron-acceptors and electron-donors in preparations with anti-COVID-19 activity is significantly higher in the comparison with compounds in the PubChem [37], approved drugs [38], natural compounds [39] and collection of small molecules that are relevant to biological systems (KEEG) [40].

Fig. 4.

The distribution of electron donors (n${}^{+}$) and electron-acceptors (n${}^{-}$) in compounds from the PubChem database [33].

Table 4.The content of the electron-donors (n${}^{+}$) and the electron-acceptors (n${}^{-}$) in the different sources of compounds.
 Source of compound Number of compounds n${}^{+}$[%] n${}^{-}$[%] n${}^{+}$+n${}^{-}$[%] TMC 93 18 29 47 AE 37 27 32 59 Polyphenols 50 0 29 29 Approved drugs 1469 8 9 17 KEEG 7638 8 9 17 Natural compounds 4668 11 16 25 PubChem 4,5010,644 4 5 9
4. Discussion

The COVID-19 pandemic is one of the greatest challenges modern medicine has ever faced. Doctors and scientists are trying to find treatments and drugs that can cure and prevent this disease. Unfortunately, nearly two years into the pandemic there is no cure yet for COVID-19 disease. A handful of therapies—remdesivir, monoclonal antibodies and the steroid dexamethasone—have improved the care of COVID patients, but these drugs are not cure-alls and they are not for everyone. On the other hand, efforts to repurpose other drugs, or discover new ones, have not had much success.

At the beginning of the COVID-19 pandemic the National Health Commission of the People’s Republic of China released the Dignosis and treatment protocol for COVID-19 which includes the TCM treatment [41]. TCM’s preventing and curative effect was outstanding. As of March 2020 new cases of COVID-19 in China have significantly decreased and more than 70,000 people were cured of COVID-19 and discharged from the hospital with the total treatment time of approximately 2 months [42]. China has today the lowest number of the daily new cases and the lowest COVID-19 mortality in the world [43].

Presented results show that most essential ingredients of analyzed TCM preparations (Table 1) can be represented by the specific groups of organic compounds according to their basic electronic properties AQVN and EIIP, and these differ from the vast majority of known chemicals which are located in BCS. These ingredients are in the domains of the AQVN/EIIP space that are situated left and right of BCS. The distribution of the essential ingredients of the important herbal pair AE (Table 2) in the AQVN/EIIP space is similar with distribution of ingredients of other analyzed TCM preparations with anti-COVID-19 activity. Previously, we reported that the domains left and right outside BCS contain the strong electron-donors and electron-acceptors, respectively [23, 24].

Polyphenols have been recently suggested as promising agents to fight COVID-19, and some clinical trials have already been approved with polyphenols to treat COVID-19. It was suggested that these compounds possess a potential immunomodulatory therapeutic value against SARS-CoV-2-induced immune response dysregulation [35]. In Table 1, the authors also analyzed emodin, a precursor of nathodyanthrones fagopyrin characterized by antiviral potential [44].

Results presented in Table 3 show that the main fraction (58%) of analyzed polyphenols with anti-COVID-19 activity are the strong electron-acceptors which are located in the AQVN/EIIP space right of BCS. Of note also is that ingredients with the electron-acceptors properties dominate in the analyzed TCM, compared to the electron-donor compounds.

Knowledge of the possible active mechanisms of TCM preparations in the treatment of COVID-19 may provide meaningful information for further study to investigate the mechanisms of TCMs as a therapeutic approach to overcoming COVID-19. TMC could treat COVID-19 through multiple components, multiple targets, and multiple pathways. Polyphenols are most abundant ingredients in all TCM preparations with the anti-COVID-19 activity. Among these polyphenols kaempferol, quercetin, baicalein and luteolin are the main components of Chinese patent medicine representing an indispensable part of TCM [33]. These flavonoids also are within natural polyphenols with demonstrated anti-COVID-19 activity [35] (Table 3).

Previously, to identify human proteins that represent the most probable candidates for interactors with flavonoids, we analyzed human proteins from the UniProt database [45], using the informational spectrum method (ISM) [46]. Results of this analysis suggest that among the human proteins NF-kB represents one of the more likely targets for flavonoids. The role of NF-kB pathway in the COVID-19 pathogenesis was confirmed in numerous studies. The investigation of the host-virus interaction provides evidence that SARS-CoV-2 modulates NF-$\kappa{}$B signaling and inflammatory cytokine expressions [47]. The experimental and in silico study suggests that compound from some TCM preparation interfere with the NF-$\kappa{}$B signaling pathway, leading to the inhibition of release of proinflammation factors, such as TNF-$\alpha{}$, IL-1$\beta{}$, IL-8 which may induce the inflammation storm in COVID-19 [48]. Zhao et al. [49] analyzed the treatment mechanism of this TCM preparation from molecular, pathway, and network levels and show in experiments in vitro that baicalin can suppres NF-$\kappa{}$B signaling and downregulate the expression of IL6 and TNF-$\alpha{}$. It was found that the SARS-CoV-2 infection activates the NF-$\kappa{}$B pathway, driving unchecked inflammation that contributes to total organ failure in COVID-19 patients [50, 51]. Based on the evidence of the role which the NF-$\kappa{}$B plays in the COVID-19 pathogenesis, this pathway was suggested as a potential target for treatment of critically ill patients [52]. We previously reported the active anti-HIV flavonoid compounds are grouped in the AQVN interval (3.34–3.59) and the EIIP interval (0.1100 and 0.1350 Ry) [53]. Of note is that this domain of the AQVN/EIIP space overlaps the domain encompassing the electron-aceptor compounds with anti-COVID-19 activity.

Quercetin represents a most investigated natural compound with the anti-COVID-19 activities. Antiviral, immunomodulatory, and anticoagulant effects of quercetin and its derivatives are recently reviewed and its potential role in prevention and management of COVID-19 were suggested [54]. It is also suggested that quercetin could prevent the cell-to-cell transmission of SARS-CoV-2 [55]. Currently, therapeutic effect of quercetin is investigated in 14 clinical studies [56].

5. Conclusions

The simple EIIP/AQVN criterion described in this paper can be used for powerful and rapid in silico screening of natural compounds that are active against SARS-CoV-2 virus and for identification and optimization of new lead compounds for treatment of the COVID-19 disease. These results, together with data from the USDA Food Database [57] (http://www.nal.usda.gov/fnic/) also can be used for selection of food and the food supplements which could have a beneficial effect for COVID-19 patients.

Author Contributions

VV and SP designed the concept. VV, MV and SG done formal analysis. VP, MV and SG performed data curation. VV and SP prepared the original draft. VV, VP, SG, MV and SP wrote and reviewed the manuscript. VP implemented the software. VV and VP done the visualization, VV and VP designed the methodology. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

This work was supported partially by John S. Dunn Endowment to SP and through Cooperative Agreement Number U01AI151801 between the National Institute of Allergy and Infectious Diseases (NIAD) and University of Texas Medical Branch/West African Center for Emerging Infectious Diseases.

Funding

This research was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia and Biomed Protection Galveston Texas USA.

Conflict of Interest

The authors declare no conflict of interest.

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