Abstract

Background: Since 2019, several critical effects of the coronavirus pandemic have surfaced, including its psychological problems such as depression. The World Health Organization has approved a group of drugs and vaccines. However, the world still faces novel coronavirus mutations, requiring more ideas to investigate a drug, vaccine and phytochemical potential chemoprevention proposal. Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV)-2 co-operates directly with the Angiotensin-Converting Enzyme 2 (ACE2) to penetrate the target cells.

Aims: We aim to introduce the possibility of studying seed oil extract as an anti-depression, anti-stress, anti-epinephrine receptor (PDB: 2rh1) and as potentially binding anti-angiotensin-converting enzyme 2 (ACE2) agent.

Methods and Methodology: We analyze the constituents of the six studied seeds’ oil with Gas Chromatography-Mass Spectrometry (GC-MS) by performing an AutoDock analysis of the components’ potential ligands to both the 2rh1 and ACE2.

Results: We observe convenient binding conformations between the investigated receptors and the 44 phytoconstituents. The AutoDock outcomes of the seeds’ phytochemical GC-MS separated components reveal highly binding energy, with ACE2 higher than 2rh1.

Conclusion: The studied seed oil contains binding energy with currently studied receptors and molecular weight, which enables it to be studied in the future as a nanoparticle against viruses, vaccines and psychiatric drugs.

Keywords

Coronavirus; Depression; Seed Oil; Adrenaline; Angiotensin-Converting Enzyme 2; Autodock; Phytochemicals; Nanoparticles

Introduction

Fruit processing produces a significant quantity of wastes. The stones of fruits such as grapes (Vitis vinifera), plum (Prunus subg. Prunus: Mirabelles), apple (Malus domestic), Ajwa dates (Phoenix dactylifera L), pomegranate (Punica granatum) and avocado (Persea Americana) are the remains that are generally discarded as trash and can cause environmental problems [1,2]. Examining such underutilized wastes’ likely dietary and therapeutic potentials will also diminish the desirable environmental waste load such as river water toxicity. Seed composition depends on maturation, the environmental cultivation state and extraction protocol method that makes about 6 to 20% of the seed oil as fatty acid, vitamin and phytosterol. The seed oil compositions vary between fatty acids (oleic, palmitic, stearic, linoleic acid), vitamins (isomers tocopherol) and phytosterol (stigmasterol), according to the method of extraction [3,4].

Recently, the global coronavirus (COVID-19) pandemic has drawn scientists’ attention to the study of possible vaccines, herb and drug treatments and protection-potential medications [5,6]. The insertion of coronavirus into susceptive cells is complicated and needs some effort to assume the receptor-binding and proteolytic mechanism of virus-cell fusion. Coronaviruses (SARSr-CoV) co-operate directly with the Angiotensin-Converting Enzyme 2 (ACE2) to penetrate the target. Studies showed that ACE2 is expressed in the mouth, tongue and lower lungs on type I and II alveolar epithelial cells, promoting viral insertions in the host [6,7]. The previous mechanism helps infuse SARS-CoV-2 entry, exploits the endogenous transcriptional machinery of alveolar cells to replicate it and spreads it into the entire lung and body, where ACE2 is expressed in other organs, including the kidney, heart and gut [5-7].

ACE-1 and ACE-2 result in cleaving angiotensin peptides into angiotensin I (Ang 1) and generating angiotensin (Ang) II. Ang II has an inflammatory response that causes vasoconstriction, bronchoconstriction, increases vascular permeability and fibrosis. These previous action responses enhance Acute Respiratory Disease Syndrome (ARDS) and lung failure in patients infected with SARS-CoV-2 and that is different to the receptor number from one individual to another.

Carboxypeptidase (zinc metalloprotease) is known as ACE2, degrading Ang II to an anti-inflammatory Ang (1-7). Ang II’s conversion to Ang (1-7) by the enzyme ACE2 produces effects that oppose the Ang II-mediated action. The SARS-CoV-2 virus infects alveolar pneumocytes by binding to ACE2, leading to a decrease in Ang II conversion to ACE2-derived peptides; for instance, a reduction in Ang (1-7) and its anti-inflammatory effects prevent the effects of Ang II and led to a higher imbalance between ACE1 and ACE2. The disturbance starts a storm of an inflammatory reaction and thus, the immune response will be overcome [6,8].

Although some animal studies proposed that the application of ACEIs could provide the inhibition of and treatment for the consequences of the COVID-19 infection, different scenarios indicate that their use may increase the infection’s deleterious conditions. Therefore, more trials need to provide evidence of their effectiveness. The potential benefit-risk study of the traditional drugs and herb extracts during COVID-19 connected with other issues such as hypertension, heart failure and gut, colon and renal disease associated with diabetes should also be discussed. Further, the psychiatric consequences during the COVID-19 pandemic should be taken into consideration [5].

A previous study reported that the coronavirus (COVID-19) pandemic produced significant distress to patients with chronic illnesses, including the emotional state and perception, especially among patients with inflammatory bowel diseases [9].

Our previous study reported that dietary intake of vitamins, especially B6, B9 and B12 and herb extracts such as agarwood significantly affect mood and stress and decrease inflammation through β2 adrenoreceptor (2rh1) binging energy [10]. Moreover, the combination of the beta-adrenergic receptor block and renin-angiotensin system inhibition throughout diminished the Ang II-induced inflammatory cascade reaction and increased Ang (1-7) as well as its anti-inflammatory effects [11-13].

We hypothesize that the seed oil extract can affect both receptors and have a potential beneficial effect in decreasing the entry of viruses in the human body, decreasing storm inflammatory outcomes and improving the mood, thus decreasing stress in the COVID-19 pandemic. From this point of view, we aim to study seed oil extract as an anti-depression, anti-stress and anti-epinephrine receptor (PDB: 2rh1) ACE2.

Material and Methods

Plant Study

Plant Materials

We obtained grape (Vitis vinifera), plum (Prunus subg. Prunus: Mirabelles), apple (Malus domestic), Ajwa dates (Phoenix dactylifera L), pomegranate (Punica granatum) and avocado (Persea Americana) seeds from fruits that were collected from a local market in Saudi Arabia for this study. Here, supplementary Fig. 1 shows the experimental design. Seeds were crushed in the crushing machine and extracted with a solvent (1: 5 w/v), where the solvent compositions were hexane and ethanol (1:1). After being soaked in the solvent for 10 minutes at room temperature (28 ± 2°C), the extracts were separately concentrated with a 40-50°C rotary evaporator 14-23. The ground seeds extracted independently with (n-hexane: absolute ethanol) as (1:1) yielded 6%, 35%, 5%, 21%, 15% and 68% oil, respectively and named as GSO(Grapes (Vitis vinifera) extracts), PSO (Plum (Prunus subg. Prunus: Mirabelles) extracts), ASO (Apple (Malus domestic) extracts), AWSO (Ajwa dates (Phoenix dactylifera L) extracts), PGSO (Pomegranate (Punica granatum) extracts), AVSO (Avocado (Persea Americana) extracts).

Figure 1: Experimental design. *Abbreviations: GSO: Grapes (Vitis vinifera) extracts; PSO: Plum (Prunus subg. Prunus: Mirabelles) extracts; ASO: Apple (Malus domestic) extracts; AWSO: Ajwa dates (Phoenix dactylifera L) extracts; PGSO: Pomegranate (Punica granatum) extracts; AVSO: Avocado (Persea Americana) extracts; GC-MS: Gas Chromatography-Mass Spectrometry; 2RH1: Epinephrine receptor; ACE2: Angiotensin-converting enzyme 2.

Gas Chromatography-Mass Spectrometry Analysis

We followed our previous method for the Gas Chromatography-Mass Spectrometry (GC-MS) analysis to separate the chemical constituents of the extract using a gas chromatography system (G3440B, Agilent Technologies, USA) [24].

The seeds extracts were re-dissolved in ethanol and filtered using a nylon 0.45 μm pore size membrane filter separately. The GC-MS analysis was performed using a general screening method [24]. The separation column was from Thermo Fisher Scientific (TR-5MS) and had the following properties: 30 m length, Internal Diameter (ID) 0.25 mm and film thickness 0.25 µm. The carrier gas was helium and the flow rate was 1 ml/min. A total of 2 µl of each sample was injected into splitless mode at an injection port with a temperature of 260ºC. The GC thermal program started at 80ºC and was conducted for 1.5 min. Next, the thermal program increased at the first ramp to 210ºC at a rate of 30ºC/min and then the rate was slowed to 20ºC/min to reach the final temperature of 320ºC; this temperature was held for 11 min. The ion source in MS was Electron Ionization (EI) and the analysis was conducted in a scanning mode with an electron energy of 70 eV. The ion source and transfer line temperatures were adjusted to 230ºC. The composites of the plant extract were identified by computer explorations in the commercial libraries of Wiley and NIST (National Institute of Standards and Technology).

We then searched the Wiley and NIST mass spectral libraries to identify the chemical components of the seeds extract [24]. Furthermore, we screened the unique seed extracts separately for components with AutoDock to determine their potential as ligands of the anti-epinephrine receptor (PDB: 2rh1) and ACE2 to provide more convincing proof of the therapeutic opportunities provided by GSO, PSO, ASO, AWSO, PGSO and AVSO [25,26].

Autodock Analysis

Preparation of the modelled epinephrine receptor (PDB: 2rh1), Angiotensin-Converting Enzyme 2 (ACE2) and specific GSO, PSO, ASO, AWSO, PGSO and AVSO components for docking

The AutoDock Vina 4.2 software includes procedures for optimizing proteins and ligands, such as allowing atomic charges to make proteins more polar [26-29]. Proteins and ligands were adjusted through the charge and rotatable bond authorization, consideration of the energy contribution of desolvation through the binding of a ligand to the protein and previous naming of grid maps of the protein surface for synergy ligands by the auto grid. These tools increase the speed and accuracy of docking with a unique scoring capacity, optimize effectively and perform the multithreading of the molecular docking [26-29].

Result and Discussion

GC-MS Analysis Outcomes

The GC-MS analysis identified the chemical composition of GSO, PSO, ASO, AWSO, PGSO and AVSO extracts. The specific components that are unique to the extract are presented in Table 1-6, which include the chemical name, molecular weight, retention time and area percentage. Besides, Table 7 illustrates the results of the GC-MS chromatogram of the selected compounds in the studied seeds, namely, GSO, PSO, ASO, AWSO, PGSO and AVSO.

Table 1: Results of the GC-MS analysis of the Grape Seed Extract (GSO).

Table 2: Results of the GC-MS analysis of the Plum Seed Extract (PSO).

Table 3: Results of the GC-MS analysis of the Apple Seed Extract (ASO).

Table 4: Results of the GC-MS analysis of the AJWA DATE SEED EXTRACT (AWSO).

Table 5: Results of the GC-MS analysis of the Pomegranate Seed Extract (PGSO).

Table 6: Results of the GC-MS analysis of the Avocado Seed Extract (AVSO).

Table 7: Results of the GC-MS chromatogram of the selected compounds in studied seeds (GSO, PSO, ASO, AWSO, PGSO and AVSO).

Docking Protein (Epinephrine Receptor PDB: 2rh1) with the Ligand (Seeds GSO, PSO, ASO, AWSO, PGSO and AVSO) Phytochemical Molecule and the ACE2 Receptor

The epinephrine receptor PDB: 2rh1 and ACE2 receptor 3D0G (Table 8) showed binding energy with the six studied seeds in the current study’s oils extracts 44 ligands (Table 9). Table 9 reflects the binding affinity of 44 ligands to both investigated receptors. These docking studies showed that among the seed extract phytochemicals, the stigmastan-3,5-diene (compound CID: 525918, MF: C29H48) component of GSO, PSO, AWSO, PGSO and AVSO had the highest binding affinity of -11.4 kcal/mole and -11.6 kcal/mole, with 2rh1 and 3D0G, respectively. Moreover, the levoglucosenone (compound CID: 699486, MF: C6H6O3) component of AWSO extract had the lowest binding affinity at -4.8 kcal/mole and 5.5 kcal/mole with 2rh1 and 3D0G, respectively, as given in Table 10. The ligands with the best possible affinity to the receptor 2rh1 and ACE2 receptor 3D0G are outlined in Table 10, while the comparison of the highest binding energy is provided in Fig. 2.

Figure 2: Comparison between the highest binding affinity (kcal/mole) interaction of 44 ligands of GSO, PSO, ASO, AWSO, PGSO and AVSO with the β2 adrenoreceptor (2rh1) and ACE2 receptor (3D0G) in the AutoDock analysis. (GSO: Grapes (Vitis vinifera) extracts; PSO: Plum (Prunus subg. Prunus: Mirabelles) extracts; ASO: Apple (Malus domestic) extracts; AWSO: Ajwa dates (Phoenix dactylifera L) extracts; PGSO: Pomegranate (Punica granatum) extracts; AVSO: Avocado (Persea Americana) extracts).

Table 8: The target receptors used in AutoDock analysis.

Table 9: Results of the GC-MS analysis of the studied seed extracts (GSO, PSO, ASO, AWSO, PGSO and AVSO) with the AutoDock analysis as potential ligand binding to the β2 adrenoceptor (2rh1) and ACE2 receptor (3D0G).

Table 10: Prediction of the best interaction of the ligands of GSO, PSO, ASO, AWSO, PGSO and AVSO with β2 adrenoreceptor (2rh1) and ACE2 receptor (3D0G) in the AutoDock analysis.

Discussion

The coronavirus pandemic has had many consequences, including health, psychological and economic consequences. The World Health Organization approved a group of drugs to treat the virus. Besides the drugs, there are ongoing races in production of vaccines. Furthermore, scientists are increasingly focusing their efforts to discover vaccines without side effects. However, the discovery of novel coronavirus mutations requires more attention and considerations and varied drugs and vaccine proposals; for example, phytochemistry potential trials.

Phytochemicals in fruits, vegetables and plant parts hold secondary metabolites and their essential metabolites have several inherent biological activities that involve antimicrobial, anti-inflammatory and inhibitory enzyme properties with health benefits [30,31]. In our previous studies, avocado and pomegranate juice, peel and seed oil ameliorated toxicity and decreased inflammation, oxidative stress and apoptosis induced by CCl4 and DEN [21,32-35].

Grape (Vitis vinifera) was introduced to the literature as a treatment after an arb doctor suggested it as a royal oil for skin treatment for Ferdinand IV in the 14^th century. It also has antioxidant and anti-inflammatory properties, according to the previous investigation. The seed composition of fruits depends on maturation, the environmental cultivation state and extraction protocol [36-38]. The results of the current study’s seed extract analysis (Table 1-7) showed that Grape Seed Oil (GSO) included 9-octadecenamide, (z)-, stigmastan-3, 5-diene, 9, 12-octadecadienoic acid (z, z)-, methyl ester, oleamide, hexadecanamide and phosphoric acid trimethyl ester. Furthermore, GSO was found to contain dodecyl acrylate, pentanoic acid, 5-hydroxy-, 2,4-di-t-butylphenyl esters, methyl stearate and 1-pentadecyne. It also included 1-pentadecyne, 11, 13-dimethyl-12-tetradecen-1-ol acetate, 4-methyl-2,4-bis(4′-trimethylsilyloxyphenyl)pentene-1, 1,3-benzenediol, o-(4-methylbenzoyl)-o’-(2-methoxybenzoyl)-, 2-bromotetradecane, cyclotrisiloxane, hexamethyl- and isooctyl 3-mercaptopropionate (Table 1).

GSO compositions such as 9-octadecenamide, (z)-, 9,12-octadecadienoic acid (z, z)-, oleamide and hexadecanamide have a sedative effect where a group of an amide of the fatty acid oleic acid is located as naturally endogenous on the animal’s body. It has an accumulation function in the cerebrospinal fluid during sleep deprivation and influences animal’s sleep, making those oleamide derivatives potential treatments for mood, depression and sleep disorders through interaction with multiple neurotransmitters. Further, it binds the Cannabinoid receptor type 1 (CB1) receptor as a full agonist. Also, these derivatives have anti-corrosive properties [39-42]. Stigmastane, 24R-ethylcholestane, is a tetracyclic triterpene and cholestane as well as ergostane. This sterane is applied as a biomarker for initial eukaryotes. Stigmastanol, Stigmastan-3, 5-diene and their derivatives are types of plant phytosterol that inhibit cholesterol absorption from the diet [43]. Acrylates are the salts, esters and conjugate bases of acrylic acid, including dodecyl acrylate, for example. They have various bifunctional functionalities such as in the polymers industry and as antimicrobial and non-chemical based antioxidant agents [44-46]. GSO also contains phosphoric acids that are not genotoxic nor carcinogenic and is therefore used as a food additive in water treatment products. Further, it is used as phosphate salts for fertilizers, dental cement, albumin derivatives and the sugar and textile industries [47].

GSO contains a group of ester, acetate and valeric or pentanoic acids; all have pleasant odors and are used in the perfume and cosmetic additives industry. Valeric acid is a minor product of the gut microbiome and can also be produced by its esters’ metabolism found in food [48,49]. The repair of these acid levels in the gut has been recommended as the mechanism in the govern of the clostridioides difficile infection after fecal microbiota transplant [49].

Methyl stearate is a fatty acid methyl ester and octadecanoate ester. Stearic acid has a role as a metabolite and is connected with reduced LDL cholesterol compared to other saturated fatty acids. It is used in lubricants, detergents, softening agents, release agents and food additives, as well as in batteries and electronic devices [50,51].

GSO contains different bioactive secondary metabolites such as sulfurous acid, 2-ethylhexyl isohexyl ester, heptacosane, dodecyl pentyl ester, eicosane 2- methyl, benzyl detervitive and 2-bromotetradecane, dodecyl acrylate as well as 1,3-benzenediol, o-(4-methylbenzoyl)-o’-(2-methoxybenzoyl)-. These combinations of secondary metabolites are related to antibacterial, antifungal and anti-diabetic attributes [52-55]. Other metabolites such as 4-methyl-2, 4-bis (4-hydroxyphenyl) pent-1-ene (MBP) have potent estrogenic action in-vitro and in-vivo; moreover, computer modelling has revealed that this greater strength is due to more effective binding to estrogen receptors. Previous studies reported that cyclotrisiloxane and hexamethyl- derivatives have antioxidant and antibacterial activity. GSO contains isooctyl 3-mercaptopropionate that depravities reported antioxidant and anti-inflammatory [56-59].

A plum is a fruit of a unique species, Prunus subg. Prunus. Plum stones include a seed with a high content of proteins and lipids that are frequently underused and undervalued. Victoria Plum Seed Oil extract (PSO) includes phytosterols such as stigmastan-3, 5-diene and hexadecanamide derivatives also found in current grape seed extract (Table 2). PSO contains esters, methyl stearate, dodecyl acrylate and benzyl detectives, which have beneficial antibacterial, anti-inflammatory, anticancer and antioxidant effects, as was discussed before concerning grape seed oil extract with the relative value of RT: Retention Times (minutes). PSO comprises squalene, a natural organic polyunsaturated hydrocarbon of the triterpene type know as shark liver oil. All plants, animals, birds and human livers provide squalene as a biochemical intermediate. It preserves polyunsaturated fatty acids against temperature-dependent autoxidation. Squalene also functions essentially as a peroxyl radical scavenger, is useful for skin hydration, works as an antioxidant, has antitumor properties and is used in cosmetics [60,61].

Apple seeds are rich in proteins, carbohydrates and minerals, making them useful as feed or fertilizer [62]. Moreover, they contain fatty linoleic acid, sterols, tocopherols, a primary fatty amid cis-11-eicosenamide and hydrocarbons, especially squalene 63, which is confirmed by the present study’s apple seed oil GC-MS analysis. Previous investigations reported that apple seed oil can improve the treatment of various diseases, especially Cardiovascular Disease (CVD) and diabetic disorder. This improvement is effected by managing the blood lipid profile, blood pressure, adipocyte hormones, inflammatory response, endothelial capacity and through numerous other beneficial effects as anticancer, antioxidant and antibacterial properties [64,65]. Moreover, dl-.alpha.-tocopherol (vitamin E) was reported as an antidepressant and significant antioxidant [63-65]. Apple Seed Oil (ASO) contains hexadecanamide, benzoic acid fatty acid esters and -octadecenoic acid and their derivatives, which have beneficial antibacterial, anti-inflammatory, anticancer and antioxidant effects, as discussed before regarding grape seed oil and plum seed oil. Apple seeds oil, also rich in fatty acids such as vaccenic acid, is an omega-7 fatty acid with antibacterial, antioxidant and anti-coronary heart disease properties [66,67]. ASO includes 2-pyrrolidinovalerophenone, which is used as a bath salt and has a neurological effect and 2-furancarboxaldehyde, 5-methyl-F, which is a derivative inhibiting sickle cell formation in the blood.

Additionally, it contains radical scavenging activity compounds such as 13-Tetradecenal. This is because plum, grape and apple seeds have a phenolic composition with antioxidant capacity, comprising 4H-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl- and 9,12-octadecadienoic acid (Z, Z)- and phenylmethyl ester [68-71].

Date palm (Phoenixdactylifera) is a member of the palm family (Arecaceae) and has been used as food for over 6000 years. It is found in Saudi Arabia, Middle Eastern countries and Egypt. Its components such as carbohydrates, phytochemicals, sterols, carotenes and flavonoids have been screened for numerous therapeutic activities and are found to decrease the side effects of manufactured medicines that hurt the human biological system. Besides, date seeds are used as animal feed or caffeine-free coffee replacements in some areas. The Ajwa date seed oil includes sterol, phytochemistry, oleic, palmitic and fatty acids and their derivatives; these have antibacterial, antioxidant, anticancer and antilipidemic effects [72,73]. The present work reported that Ajwa date seed oil (AWSO) contains hexadecanamide, 5-hydroxymethylfurfura, 9-octadecenamide, (Z)-, oleic acid, cis-11-eicosenamide, dodecanoic acid and palmitic acid. Squalene and stigmastan-3,5-diene are found in it. AWSO contains fatty acid ester, other phenol and furfural derivatives, as presented in Table 4. These compounds have antioxidant and anti-inflammatory, neurological, sedation and cosmetic effects. Moreover, it contains 7-methyl-Z-tetradecen-1-of acetate, which has the effect of heat and heat cough [74].

The present work reported that pomegranate (Punica granatum L.), which belongs to the Punicaceae famil (PGSO), contains hexadecanamide, 5-hydroxymethylfurfural, 9-octadecenamide, (Z)-, oleamide, cis-11-eicosenamide, dodecyl acrylate and fatty acid ester, as well as phenol, squalene, stigmastan-3,5-diene (Table 5). These compounds have antioxidant and anti-inflammatory effects [19]. Avocados (Percea Americana) are related to the Lauraceae family. Avocados contain carotenoids, minerals, phenolics, vitamins and fatty acids. Further, avocados have lipid-lowering, antihypertensive, antidiabetic, anti-obesity, antithrombotic, antiapoptosis and anti-atherosclerotic cardio-protective effects. The avocado seeds are considered one of the fruit’s non-edible parts, which are generally discarded as trash and can cause environmental problems. Examining such foods’ underutilized dietary and therapeutic potential will also diminish the environmental waste load [33,75].

The composition of avocado seed includes protein, fat, ash, moisture, fiber and carbohydrate, minerals such as Ca, Zn, K, Na, P, Fe, Cu, Pb and Co) phytochemicals (flavinoid, tanine, saponine, total phenolics, antioxidant capacity, oxalates, phytates and alkaloids) and vitamins (A, B1, B2, B3, C and E). The avocado seeds have antioxidant and antimicrobial, antihypertensive, fungicidal, larvicidal, hypolipidemic, amoebicidal and giardicidal activities [76].

The present study indicated that AVSO contains many fatty acids and their derivatives (Table 6), such as linoleyl alcohol and carboxamide derived from palmitic acid and volatile compounds, for example, cyclodecacyclododecene, 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18-octadecahydro-, hexadecanamide, 9-octadecenamide, (Z)-, 2H-pyran and 2-(7-heptadecynyloxy)tetrahydro. AVSO includes steroids such as androstan-17-one, 3-ethyl-3-hydroxy-, (5.alpha.) and the polycyclic aromatic hydrocarbon chrysene, octadecahydro. Also, its composition of 11-eicosenoic acid, monounsaturated omega-9 fatty, dl-.alpha.-tocopherol and gamma.-tocophero shows antioxidant activity. AVSO includes bicyclic organic compounds such as bicyclo[10.6.0]octadeca-1(12),15-diene as well as antitumor cis-10-nonadecenoic acid, monounsaturated fatty cis-10-nonadecenoic acid [77-79].

AVSO contains many essential and volatile oils, ester derivatives, farnesol isomer, heptacosane and 3-chloropropionic acid, heptadecyl este. Caryophyllene oxide has chemopreventative, anti-tumor and antifungal properties and is used in approved food flavoring and other benzyl, organic and aromatic derivatives, as indicated in Table 6 [80,81]. It yields antioxidant compounds such as oleic acid, stigmastan-3,5-diene and antifungal cosmetics agents such as sclaral (sclareolide lactol) [82].

Molecular docking is a theoretical simulation system based on bioinformatics, which depends on the cooperation between molecules (such as ligands and receptors) and predicts their binding modes and affinity by computer investigation. Molecular docking works as an acceptable tool in medicinal chemistry for fields such as structure-based analytical drugs. Various original studies corresponding to biomolecular cooperation in food pattern and phytochemistry have continuously evolved. The remarkable benefits of molecular docking, such as predicting procedures with fewer experiments and limiting the decline of material in trials, have led to the consideration of its possible administration in various areas. In docking complex binding energy, the lowest energy positions designate the highest binding affinity, as high energy creates variable conformations that assist in pharmacological experiments. Our previous work on rat and human investigations showed that the treatment effect of vitamin B and agarwood extracts confirmed by molecular docking might be due to their role as inverse agonists, reversing the induction of stress and depression by epinephrine with many medicinal properties, such as sedative, anti-inflammatory and anti-apoptotic effects [10]. The present work described the investigated compounds in the seed extracts have a potential binding mode with the β2 adrenoreceptor (2rh1) and ACE2 receptor (3D0G) by docking analysis (Table 9,10). Further, the inhibitory effect of synergetic extract compounds was also reported. The present finding established the seed compounds’ ameliorating effect against both studied receptors and might represent the studied extract as an inverse agonist ligand for depression and infection in the COVID-19 pandemic.

We have future application possibilities in using the currently investigated seed oil extracts in manufacture as endogenous nanoparticles as drugs carrier or vaccines to target cell receptors and prolong their circulation time. Moreover, as the seed oil extract is present in fruit and is edible, it will help decrease the side effects that are likely to occur due to nanoparticles, vaccines and drugs in the surrounding and body tissue.

Many bioactive phytochemicals and herbal medicines have low solubility in aqueous media, poor bioavailability, poor stability and toxicity-dose dependence, so scientists have used nanotechnology to overcome these disadvantages and deliver bioactive phytochemicals to the target with higher efficiency, using encapsulation. For this goal, nanoparticles can be provided in various forms, sizes and combinations and adjusted physicochemically to accomplish particular characteristics, depending on the features of both the bioactive molecule and the target cell, such as an inorganic gold atom (molecular weight = 196.96657 g/mol) or organic liposome (molecular weight = 938.1 g/mol). Unfortunately, there are challenges such as the potential toxicity of nanoparticles, such as immunotoxicity, the toxicity of surfactants and co-surfactants or emulsifier nanocarriers, long-term toxicity due to chronic exposure and the accumulation as well as overaccumulation of nanoparticles at all barriers before acting on the targeted cells. The analyzed seed oil contents’ binding energy with the currently studied receptors enables them to be future nanoparticles in vaccines and drugs. Further, the molecular weight allows them to be nanocarriers [83-86].

Conclusion

In this investigation, the binding interactions of 44 phytoconstituents were carried out against the β2 adrenoreceptor (2rh1) and the ACE2 receptor, 3D0G. All the currently studied seed oil extract constituent were identified by gas chromatography-mass spectrometry and studied. The present investigation strongly suggests the application of these seed oil extracts to ameliorate depression and decrease and prevent infection in the COVID pandemic. Further studies need to be carried out to examine these compounds’ pharmacological properties and inhibitory potentials require experimental models.

Author Contributions

A.F.H. contributed to creating and owning, conceptualizing, work idea designing and performing the experiments, chromatography and AutoDock analysis, interpreting and analyzing data, writing, revising and editing the manuscript and explaining the results. T.M.F. contributed to the AutoDock analysis and formatting manuscript. I.M.A, I.A.K, M.E.O, M.A.A and F.M.A. contributed to the doing practical of the chromatography portion of the study.

Ethical Statement

This research did not include any human subjects or animal experiments.

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