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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 5  |  Page : 43-50

Activity of phytochemical constituents of black pepper, ginger, and garlic against coronavirus (COVID-19): An in silico approach


Department of Pharmaceutical Chemistry, JSS College of Pharmacy, (A Constituent College of JSS Academy of Higher Education and Research - Deemed University), Ooty, Nilgiris, Tamil Nadu, India

Date of Submission20-Apr-2020
Date of Decision06-May-2020
Date of Acceptance13-May-2020
Date of Web Publication04-Jun-2020

Correspondence Address:
Dr. Kalirajan Rajagopal
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, (A Constituent College of JSS Academy of Higher Education and Research - Deemed University), Ooty - 643 001, Nilgiris, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhas.IJHAS_55_20

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  Abstract 


BACKGROUND: In early 2020, many scientists are rushing to discover novel drugs and vaccines against the coronavirus, and treatments for coronavirus disease 2019 (COVID-19), because, the disease which was named as COVID-19, a life-threatening viral disease affected first in china and quickly spread throughout the world.
OBJECTIVE: In the present article, in silico studies have been performed to explore the binding modes of chemical constituents for natural remedies such as pepper, ginger, and garlic against COVID-19 (PDB id-5R82) targeting coronavirus using Schrodinger suit 2019-4.
METHODS: The docking studies are performed by Glide module, in silico ADMET screening was performed by qik prop module and binding energy of ligands was calculated using Prime Molecular Mechanics-Generalized Born Surface Area module.
RESULTS: From the results, the chemical constituents from pepper like Piperdardiine, Piperanine and from ginger like 8-Gingerol, 10-Gingerol, significantly active against COVID-19 with significant Glide score when compared to currently used drug Hydroxychloroquine (-5.47). The docking results of the compounds exhibited similar mode of interactions with COVID-19, and the residues SER46, MET49, HIE41, GLN189, ARG189, ASP187, MET165, HIE164, THR24, THR25, LEU27, ASN142, and GLY143 play a crucial role in binding with ligands.
CONCLUSION: The chemical constituents from pepper such as Piperdardiine, Piperanine, and from ginger like 8-Gingerol, 10-Gingerol are significantly active against COVID-19 which are useful for further development.

Keywords: Coronavirus-19, docking studies, garlic, ginger, molecular mechanics-generalized born surface area, pepper


How to cite this article:
Rajagopal K, Byran G, Jupudi S, Vadivelan R. Activity of phytochemical constituents of black pepper, ginger, and garlic against coronavirus (COVID-19): An in silico approach. Int J Health Allied Sci 2020;9, Suppl S1:43-50

How to cite this URL:
Rajagopal K, Byran G, Jupudi S, Vadivelan R. Activity of phytochemical constituents of black pepper, ginger, and garlic against coronavirus (COVID-19): An in silico approach. Int J Health Allied Sci [serial online] 2020 [cited 2020 Jul 13];9, Suppl S1:43-50. Available from: http://www.ijhas.in/text.asp?2020/9/5/43/285960




  Introduction Top


Coronavirus disease 2019 (COVID-19) is a life-threatening viral disease which was affected first in China and quickly spread throughout the world. According to the WHO data, as on April 3rd week of 2020, there are more than 24 lakhs peoples in the world affected by COVID-19, out of these; more than 1.65 lakhs peoples are died. With more asymptomatic infections being found among COVID-19 cases, it is worthy of consideration, the detail current evidence, and understanding of the transmission of SARS-CoV, MERS-CoV, and SARS-CoV-2 and discuss pathogen inactivation methods on coronaviruses is very important.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10] In this emergency situation, it is very difficult to discover novel drugs with all clinical trials and also check the side effects, adverse effects, etc., Hence, it is important to treat with some natural remedies which are using regularly in our diet for COVID-19. The natural products such as Black pepper (Piper nigrum), Ginger (Zingiber officinale), and Garlic (Allium sativum L.) which are regularly used in our diet and also have various biological activities.

Ginger (Z. officinale) was reported for protect gastric mucosa against several ulcerogenic agents and is very useful in cases of ulcerogenesis because of its antioxidant properties anti-cholinergic and anti-histaminic receptors.[11],[12] Ginger also modulates genetic pathway, acts on tumor suppression of genes,[13] good anti-platelet and cyclooxygenase I inhibitory propertie,[14] anti-inflammatory action on prostaglandin synthesis also help in relieving menstrual cramps antimicrobial effect,[15] cholesterol regulation, and hypotensive properties,[16] etc.

Garlic (A. sativum L.) was reported for abdominal discomfort, diarrhea and respiratory tract infections,[17] and antimicrobial drugs.[18] Antioxidant, anti-inflammatory, and anti-stress properties,[19] anti-cancer[20] cardiovascular disease,[21] anti-diabetic property,[22] immunity booster,[23] and antimicrobial effects,[24] etc.

Black pepper (P. nigrum) was reported for anti-cancer,[25] antioxidant, cardiovascular disease,[26] respiratory congestion, helping to expectorate, and dry up mucus membranes[27] physiological effects,[28] etc.

As a part of our ongoing research on searching the potent biological molecules against various disease by in silico and wet laboratory methods,[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39] we have designed and evaluated various heterocyclic scaffolds for their biological activities. Using different modules (Glide, Qikprop, and Prime) of Schrödinger suite various computational methods like molecular docking, ADMET screening and binding free-energy calculations were performed to find the interactions responsible for COVID-19 inhibition. These studies will provide the requirement of key structural features in the design of potential drug candidates.


  Methods Top


The three-dimensional crystal structure of COVID-19 protein called SARS-CoV-2 main protease receptor cocrystallized with 6-(ethylamino) pyridine-3-carbonitrile (PDB ID: 5R82, Resolution: 1.31 Š) was retrieved from the protein data bank. The protein was prepared using protein preparation wizard of epic module[40] of Schrödinger suite 2019-4. The initial protein structure is a monomer, having similar binding sites were removed with deleting waters, refining bond orders, and addition of hydrogen's. Missing chain atoms are added by[41] using the Prime module of Schrödinger suite 2019-4. Protein minimization was performed using Optimized Potentials for Liquid Simulations 3 molecular force field with root mean square difference (RMSD) of crystallographic heavy atoms kept at 0.30 Š. A grid box was generated to define the centroid of the active site. All the compounds were docked into catalytic pocket of COVID-19 by using Glide module of Schrödinger suite 2019-4 in extra precision (XP) mode.[42] The binding modes with best glide G score were selected. To predict the free energy of binding for the set of ligands in complex with receptor a postdocking energy minimization studies were performed using Prime Molecular Mechanics-Generalized Born Surface Area (MM-GB/SA) of Schrödinger 2019-4. The energy for minimized XP docked pose of ligand receptor complex was calculated using the OPLS3 force field and MM-GB/SA continuum VSGB 2.0 solvent model.[43]


  Results and Discussion Top


The results are summarized in [Table 1], [Table 2], [Table 3] and [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]. The results revealed that the COVID-19 inhibitory property of the compounds isolated from some natural products such as black pepper, ginger, and garlic, greatly depended on the chemical nature of the substituents. The chemical structures of selected major bioactive constituents of ginger, black pepper, and garlic are given in the [Figure 1]a, [Figure 1]b, [Figure 1]c.
Table 1: Docking studies for phytochemical constituents of black pepper, ginger, and garlic with coronavirus disease 2019 (5R82)

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Table 2: In-silico ADMET screening for chemical constituents of pepper, ginger, and garlic

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Table 3: Binding free energy calculation using prime/MM-GBSA approach

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Figure 1: (a) Chemical structures of selected major bioactive constituents of black pepper (Piper nigrum). (b) Chemical Constituents of Garlic (Allium sativum L.). (c) Chemical-structures of selected major bioactive constituents of ginger (Zingiber officinale)

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Figure 2: Docked poses of all compounds with COVID19 (5R82)

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Figure 3: (a) Ligand Interaction of compound P6_Piperdardiine with coronavirus disease 2019 (5R82). (b) Ligand interaction of compound Z3_8Gingerol with coronavirus disease 2019 (5R82). (c) Ligand interaction of compound Z4_10Gingerol with coronavirus disease 2019 (5R82). (d) Ligand interaction of compound P2_Piperanine with coronavirus disease 2019 (5R82)

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Figure 4: Best affinity mode of docked compounds with coronavirus disease 2019 (5R82)

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Figure 5: Hydrogen bonding interaction of cpd Z3_8Gingerol with coronavirus disease 2019 (5R82)

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Figure 6: Hydrophilic/lipophilic map of cpd P6_Piperdardiine with coronavirus disease 2019 (5R82)

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Figure 7: Rotational penalty of Compound Z1_6Shogaol with coronavirus disease 2019 (5R82)

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The docking studies of the ligands to protein active sites were performed by an advanced molecular docking program Glide module of Schrodinger suite 2019 Maestro-12.2 version for determining the binding affinities of the compounds. The designed analogs were docked toward the COVID-19 (PDB id: 5R82) to ascertain their inhibitory activity. The analogs show best fit rmsd value of 0.2. As shown in [Table 1], it is clearly demonstrated that some of the chemical constituents from black pepper such as piperdardiine, piperanine, and from ginger like 8-Gingerol, 10-Gingerol, are significantly active against COVID19 with significant Glide score more when compared to currently used drug hydroxychloroquine (−5.47). The above compounds have good affinity to the receptor due to more lipophilic character and also due to hydrogen bonding.

The results are summarized in the [Table 1]. The best-affinity modes of all the docked compounds with COVID-19 (PDB id: 5R82) are shown in [Figure 2]. Almost all the compounds are docked in the same binding pocket.

The docking results of the compound P6_Piperdardiine exhibited interactions with COVID19 and the residues SER46, MET49, HIE41, GLN189, ARG189, ASP187, MET165, HIE164, THR24, THR25, LEU27, ASN142, and GLY143 play a crucial role in binding with ligands The 2D-ligand interaction diagram of P6_Piperdardiine, Z3_8-Gingerol, Z4_10-Gingerol, and P2_Piperanine are given in the [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d.

From the molecular-docking study, it was revealed that the ligands have shown agreeable glide G score values from −4.8 Kcal/mol (Z1_6-Shogaol) to −5.95 Kcal/mol (P6_Piperdardiine) From the obtained binding modes, it was illustrated that the ligands formed hydrogen bonding and hydrophobic interactions with different residues THR24 to GLN189 surrounding the active pocket which was shown in [Figure 4]. The ligand Z3_8Gingerol exhibited hydrogen bonding interaction with Leu27 (H-Bond lengh 6.15 A°), HIE41 (H-Bond lengh 6.13 A°) residues and with some water molecules are shown in the [Figure 5]. The presence of aromatic features and different heterocyclic rings majorly contributed toward lipophilic factors from the supplementary [Figure 6].

The G-score of some compounds are decrease because on some negative parameters such as XP penalties, rotational penalties, etc., The rotational penalty of Compound Z1_6-Shogaol is shown in [Figure 7].

The ADMET screening for the molecules can be predicted in silico by using qikprop module of Schrödinger suite 2019-4. From the in silico ADMET screening results of all the compounds are within the recommended values. The results of the ADMET properties for compounds are shown in [Table 2].

Molecular docking was additionally assessed with MM-GBSA free-restricting vitality which is identified with the postscoring approach for COVID19 (PDB ID: 5R82) target and the values are shown in the [Table 3]. From the results of MM-GB/SA studies the dG bind values were observed in the range of −22.27 (Z1_6-Shogaol) to −42.947 Kcal/mol (Z4_10-Gingerol) and also dG vdw values, dG lipophilic values and the energies are positively contributing toward total binding energy. The accuracy of docking is confirmed by examining the lowest energy poses predicted by the scoring function. The Glide score and MM-GBSA free energy are obtained by the docking of ligands into the coupling pocket are more stable.


  Conclusion Top


From the results of docking study that chemical constituents of black pepper, ginger, and garlic demonstrated better arrangement at dynamic site. The in silico structuring strategy embraced in the present investigation helped for recognizing some lead molecules and furthermore may somewhat clarify their useful impact for further determinations likein vitro andin vivo assessments. The results from the in silico study exhibited that many of the chemical constituents from black pepper and ginger family may be useful against COVID-19. The chemical constituents of black pepper such as Piperdardiine, Piperanine, and ginger such as 8-Gingerol and 10-Gingerol are significantly active against COVID-19 with remedial possibilities and are probably going to be helpful after further refinement. In conclusion, consuming of black pepper and ginger in our diet regularly may be useful remedy in the prevention of corona virus.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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