Research Article
 

Investigation on the Impact of Potential Phytocompounds from Curcuma longa Against COVID-19



D. Jini, R.M.H. Rajapaksha, S.S. Ariya and Baby Joseph
 
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ABSTRACT

Background and Objective: COVID-19 is a new viral infectious disease caused by SARS-CoV-2 and there are no vaccines or drugs available to treat this deadly disease. Curcuma longa is a well-known medicinal plant with the antiviral property. So, the present study aims to evaluate the antiviral activity of phytocompounds from Curcuma longa against SARS-CoV-2. Materials and Methods: The phytocompounds from the Curcuma longa were docked with the main protease of SARS-CoV-2 (SARS-CoV-2 Mpro) by Autodock 4.2 to analyze the possibility of inhibiting the SARS-CoV-2 Mpro. Protein-ligand interaction profiler and ligplot+v.1.4.5 were used to analyze the interactions between the ligand and protein molecules. The toxicity and pharmacophore of the phytocompounds were determined by SWISSADME and PharmaGist web server. Results: Among the 85 and 20 compounds showed binding energy in the range of -10.12 to -7.52 which were considered as active compounds against SARS-CoV-2. Beta-Carotene was the highest active compound with the binding energy of -10.12 kcal mol1. All the 20 active compounds interacted with the LYS5 and TYR126 amino acid residues of SARS-CoV-2 Mpro through hydrophobic and hydrogen bond interaction except Beta-Carotene. Moreover, all the 20 active compounds are present in the rhizome of Curcuma longa and are obeying Lipkin’s rule except Beta-Carotene. Conclusion: Based on the binding energy score, all the active compounds can be suggested to test against COVID-19. In addition, the rhizome of Curcuma longa can be recommended as a potential herbal medicine for the treatment of COVID-19.

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  How to cite this article:

D. Jini, R.M.H. Rajapaksha, S.S. Ariya and Baby Joseph, 2022. Investigation on the Impact of Potential Phytocompounds from Curcuma longa Against COVID-19. Journal of Plant Sciences, 17: 33-52.

DOI: 10.3923/jps.2022.33.52

URL: https://scialert.net/abstract/?doi=jps.2022.33.52
 

INTRODUCTION

COVID-19, a severe pandemic disease, caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus 2), spread all over the world and killed several human lives since December, 20191. COVID-19 first appeared in the Wuhan city of China in late 2019 and has transformed into a confirmed global pandemic in all countries of the world within a short time2. SARS-CoV-2 tends to be extremely infectious and transfers primarily from human to human through the fomites and the respiratory droplets of infected individuals3. To accelerate the development of new medicines to inhibit the spread of SARS-CoV-2, numerous existing antiviral drugs were tested for their effectiveness against SARS-CoV-24.

Currently, no drugs or vaccines are available against COVID-19 to hinder or prevent the spreading of disease because of the limited knowledge on the molecular understanding of the SARS-CoV-2 infection. In the positive sense, the single-strand long RNA genome present in the SARS-CoV-2 encodes a large number of structural and nonstructural proteins. Diverse host receptors for the viral entry, non-conserved domains of antigens and the high rate of mutation and recombination are the major issues in the development of drugs and vaccines against SARS-CoV-25. The main protease of SARS-CoV-2 (SARS-CoV-2 Mpro) is playing a major role in the viral gene expression and replication with a highly conservative active site6. These main proteases are involved in the cutting of large polypeptides synthesized by the RNA of SARS-CoV-2 which made them become functional7. So, viral replication and growth can be inhibited by blocking the main protease of SARS-CoV-28. Numerous studies were conducted to identify the three-dimensional structure of SARS-CoV-2 Mpro through X-ray crystallographic techniques and several crystal structures were available in the Protein Data Bank (PDB). This SARS-CoV-2 Mpro protein becomes a potential target for the inhibition of SARS-CoV-2 replication9.

Recently numerous computational studies were conducted to develop drugs or vaccines against SARS-CoV-210,11. Some researchers have explored the potential effects of human immunodeficiency virus protease inhibitors such as lopinavir and ritonavir to treat COVID-19 patients12. The chemical compounds from the Indian spices were screened for the inhibition of SARS-CoV-2 main protease by bioinformatics approaches13. A data-driven approach was employed to analyze the blocking ability of Chinese medicine against SARS-CoV-2 main protease14. Molecular docking was used to screen the natural compounds from various medicinal plants against COVID-19 by targeting SARS-CoV-2 main protease15. Virtual screening and machine learning approaches were applied to identify novel drug candidates against SARS-CoV-2 main protease from the FDA-approved drugs, natural compound datasets and the ZINC database16. Even though there are many drug candidates were suggested through the bioinformatics approach, the pharmacokinetic and pharmacodynamic properties of the identified molecules were not clear for treating the COVID-19 patients. Therefore, exploring the natural compounds can pave the way for the identification of safe and novel anti-coronaviral compounds for treating COVID-19.

Indian traditional medicine systems have been using more than 45,000 species of plant17 which are playing a vital role in the inhibition of various viral diseases like dengue18, chicken guinea19 and swine flu20. The people in most of the developed and squat deadlift-earning countries depend on traditional medicines for their primary health care21. People in India are using medicinal plants for the habitual cure of severe diseases including diabetes and cancer22,23. Indian medicinal plants were also examined for various antiviral properties24,25. The Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy (AYUSH), India recommended various medicinal plants such as Ocimum tenuiflorum, Cinnamomum verum, Piper nigrum, Zingiber officinale and Vitis vinifera to boost the immunity against COVID-19. The spices used in India were also screened for the identification of potential drugs against COVID-1912.

Curcuma longa (Turmeric) is a widely used Indian spice that belongs to the ginger family26, has been demonstrated to have antibacterial, anti-inflammatory, antioxidant, antihyperlipidemic and anti-neoplastic effects27,28. Curcuma longa has been utilized from time immemorial as a cure in Indian traditional and folk medicine to treat several illnesses such as arthritis, fever, jaundice, trauma, ulcers, wounds and psoriasis29. The various extract of Curcuma longa has been shown to exhibit antiviral properties against numerous viral diseases30,31. Curcumin is a well-studied component of Curcuma longa, has been proved to have numerous functions in inhibiting or treating several diseases, including viral infections and cancer32. Zahedipour et al.33 reviewed the antiviral effects of curcumin and suggested that curcumin could be used as a potential remedy for the treatment of coronavirus disease. The Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy (AYUSH), India recommended using turmeric (Curcuma longa) powder (half a teaspoon) in hot milk (150 mL) once or twice a day to develop the immunity against COVID-19 without any scientific evidence.

Coronavirus has become a major challenge for every country at present. Because we know that no drugs are available to treat or prevent the disease, we can use some natural products which can be helpful to avoid the Coronavirus spread, which is better, at the same time they can improve natural immunity. Herbal medicines or natural compounds can be used both to prevent viral ailment and to stop the spread of infection. The present study mainly focused on the inhibition of SARS-CoV-2 main protease (SARS-CoV-2 Mpro) by using natural products to find novel ameliorates that can be used as a drug or medicine against Coronavirus. The rhizome of Curcuma longa is the commonly used natural product as a food or medicine against various ailments. To evaluate the anti corona viral activity of Curcuma longa, a library containing 85 phytocompounds from Curcuma longa was constructed. These phytocompounds were subjected to molecular docking analysis against SARS-CoV-2 Mpro and the active compounds were identified.

MATERIALS AND METHODS

Study area: The study was carried out at the Department of Biotechnology, Malankara Catholic College, Mariagiri, Kaliakkavilai, Tamil Nadu, India from June, 2019 to June, 2021.

Ligand preparation: The compounds present in the Curcuma longa was identified from a literature search and Dr. Dukes Phytochemical and Ethnobotanical database (https://phytochem.nal.usda.gov/phytochem/search/list).

The identified compounds were searched in PubChem and ZINC databases for the retrieval of 3D structure in SDF format. The Open Babel software was used for the conversion of all the 3D structures in SDF format into PDB format. The structure of hydroxychloroquine (3652) was taken as the reference molecule for the comparison of the activity.

Protein preparation: The UniProt database was used to identify the structure of SARS-CoV-2 Mpro. The crystal structure of a protein was selected based on the lowest resolution and the amino acids in Ramachandran plot. The 3D structure of the selected protein was downloaded from the PDB (https://www.rcsb.org) database. The heterogeneous atoms and the water molecules present in the protein were removed by using MG Tools of AutoDock 4 and the PDB format of the protein was made for molecular docking analysis.

Molecular docking: All the docking analysis were performed by AutoDock 4.2 software with the optimized docking parameters34. The polar hydrogen atoms and Kollman united atom type charges were added to the protein molecule and it was saved in PDBQT format. The energies of the 85 phytocompounds were minimized by adding the Gasteiger partial charges, merging the non-polar hydrogen atoms and defining the rotatable bonds. The grid maps were constructed with the spacing of 0.375 Å and the dimensions of 80×80×80 Å by using AutoGrid. Lamarckian genetic algorithm 4.2 was employed for molecular docking. The phytocompounds with the activity of less than -7.5 will be selected as the highly active compounds for the interaction analysis. Protein-ligand Interaction Profiler and Ligplot+ v.1.4.5 software were used to analyze the interactions between SARS-CoV-2 Mproprotein and the active compounds.

Drug-likeness properties and pharmacophore study: Since the Curcuma longa was always ingested orally, an in silico integrative model of Absorption, Distribution, Metabolism and Excretion (ADME) was used to screen for natural compounds that may be bioactive via oral administration. SwissADME35 was used to analyze the drug-likeness and the ADME properties of the highly active compounds from the docking studies. PharmaGist webserver36 was used to study the important pharmacophore features of the active compounds and the reference molecules (Hydroxychloroquine).

RESULTS AND DISCUSSION

Ligand and protein preparation: In Curcuma longa, there are 267 compounds available in the Dr. Dukes Phytochemical and Ethnobotanical Database. Among the 267 compounds, the overlapping compounds were removed and the remaining 170 compounds were subjected to retrieve the 3D structure from the PubChem and ZINC databases. The availability of 170 compounds in various parts of Curcuma longa was given in Table 1. The structure of 85 compounds is only available in the PubChem database which was retrieved and used for the docking analysis (Table 2). Since hydroxychloroquine was recommended to treat the COVID-19 patients through clinical trial37, it was used as a reference molecule in this study.

The main protease of SARS-CoV2 (SARS-CoV-2 Mpro) is composed of 306 amino acids and is 33.83 kDa in size (theoretical). The crystal structure with the PDB ID of 6Y84 was selected as SARS-CoV-2 Mpro from the UniProt database (ID: PODTD1) based on the low resolution (1.35 A) and the amino acids in the core, allowed and disallowed regions of the Ramachandran plot. Since the SARS-CoV-2 Mpro protein becomes a potential target for the inhibition of SARS-CoV-2 replication, several researchers crystallized the protein and deposited their structure in the Protein Data Bank (PDB).

Table 1: Compounds in the Curcuma longa plant parts
Compounds Plant parts Compounds Plant parts
(+)-(S)-Ar-turmerone Rhizome D-Sabinene Rhizome
(+)-Ar-turmerone Rhizome Dehydrocurdione Rhizome
(+)-Sabinene Root, rhizome essential oil Dehydroturmerone Rhizome
1,5-Bis-(4-Hydroxy-3-Methoxy-Phenyl)-Penta-Trans-1-Trans-4-Dien-3-One Rhizome Demethoxycurcumin Root, plant, rhizome
1,5-Bis-(4-Hydroxy-3-Methoxyphenyl)-1,4-Pentadien-3-One Rhizome Desmethoxycurcumin Rhizome
1,7-Bis-(4-Hydroxy-3-Methoxyphenyl)-1,4,6-Heptatrien-3-One Rhizome Di-P-Coumaroyl-Methane Rhizome
1,7-Bis-(4-Hydroxy-Phenyl)-Hepta-1,4,6-Triene-3-One Rhizome Dicinnamoylmethane Rhizome
1,7-Bis-(4-Hydroxyphenyl)-1-Heptene-3,5-Dione Rhizome Didesmethoxycurcumin Rhizome
1,8-Cineole Leaf, rhizome, root Diferuloyl-Methane Rhizome
1-(4-Hydroxy-3-Methoxy-Phenyl)-5-(4-Hydroxy-Phenyl)-Penta-Trans-1-Trans-4-Dien-3-One Rhizome Dihydrocurcumin Rhizome
1-(4-Hydroxy-3-Methoxy-Phenyl)-7-(3,4-Dihydroxy-Phenyl)-Hepta-1,6-Diene-3,5-Dione Rhizome Epi-Procurcumenol Rhizome
1-Hydroxy-1,7-Bis-(4-Hydroxy-3-Methoxyphenyl)-6-Heptene-3,5-Dione Plant Eugenol Essential oil, tuber, rhizome essential oil
2,5-Dihydroxy-Bisabola-3,10-Diene Rhizome Fat Rhizome, plant
2-Bornanol Plant Feruloyl-4-Hydroxycinnamoyl-Methane Plant
2-Hydroxy-Methyl-Anthraquinone Rhizome Feruloyl-P-Coumaroyl-Methane Rhizome
4''-(3''-Methoxy-4''-Hydroxyphenyl)-2''-Oxo-3''-Enebutanyl-3-(3'-Methoxy-4'-Hydroxyphenyl)-Propenoate Rhizome Flavonoids Rhizome
4(S)-5(S)-Epoxy-Germacrone Rhizome Fructose Rhizome
4-Hydroxy-Bisabola-2,10-Dien-9-One Rhizome Gamma-Atlantone Root, rhizome
4-Hydroxy-Cinnamoyl-(Feruloyl)-Methane Rhizome Gamma-Terpinene Rhizome, leaf
4-Hydroxy-Feruloxyl-Methane Rhizome Germacrene Rhizome
5'-Methoxy-Curcumin Rhizome Germacron-(4s',5s)-Epoxide Rhizome
5-Hydroxy-4-Methoxy-Bisabola-2,10-Dien-9-One Rhizome Germacron-13-Al Rhizome
5-Hydroxy-Procurcumenol Rhizome Germacrone Rhizome
Alpha-Atlantone Root, rhizome Glucose Rhizome
Alpha-Curcumene Rhizome Guaiacol Rhizome
Alpha-Phellandrene Rhizome, root, root essential oil, rhizome essential oil, leaf Guaiane Rhizome
Alpha-Pinene Leaf, essential oil, rhizome essential oil, rhizome, tuber Iron Rhizome plant
Alpha-Terpinene Rhizome, Leaf Isoborneol Rhizome essential oil
Alpha-Terpineol Rhizome Isoprocurcumenol Rhizome
Alpha-Tocopherol Root L-Alpha-Curcumene Rhizome
Alpha-Turmerone Rhizome L-Beta-Curcumene Rhizome
Ar-Turmerone Rhizome essential oil, root rhizome Limonene Tuber, essential oil, rhizome essential oil, leaf, rhizome
Arabinose Rhizome Linalol Essential oil
Ascorbic-Acid Rhizome, plant Linalool Rhizome, tuber, rhizome essential oil
Ash Rhizome, plant Magnesium Plant
Azulene Rhizome Manganese Rhizome, plant
Beta-Bisabolene Rhizome Monodemethoxycurcumin Root, rhizome
Beta-Carotene Plant, rhizome Niacin Plant, rhizome
Beta-Pinene Leaf, rhizome, rhizome essential oil, Nickel Rhizome
Beta-Sesquiphellandrene Rhizome O-Coumaric-Acid Leaf, rhizome
Beta-Sitosterol Root, rhizome P-Coumaroyl-Feruloyl-Methane Rhizome
Beta-Turmerone Rhizome P-Cymene Leaf, rhizome
Bis-(4-Hydroxy-Cinnamoyl)-Methane Plant, rhizome P-Methoxy-Cinnamic-Acid Rhizome
Bis-(P-Hydroxy-Cinnamoyl)-Methane Rhizome P-Tolyl-Methylcarbinol Rhizome
Bis-Demethoxycurcumin Root, plant, rhizome P-Tolymethylcarbinol Rhizome
Bisabola-3,10-Dien-2-One Rhizome Phosphorus Rhizome, plant
Bisabolene Root Phytosterols Root
Bisacumol Rhizome Potassium Rhizome, plant
Bisacurone Rhizome Procurcumenol Rhizome
Borneol Rhizome, root, rhizome essential oil Protein Plant, rhizome
Boron Root Protocatechuic-Acid Leaf
Caffeic-Acid Rhizome Quercetin Rhizome
Calcium Rhizome, plant Resin Rhizome
Calebin-A Rhizome Riboflavin Rhizome, plant
Campesterol Rhizome, root Salicylates Root
Camphene Rhizome Saturated-Fatty-Acids Rhizome
Camphene Tuber Selenium Plant
Camphor Rhizome essential oil, tuber Silicon Plant
Caprylic-Acid Rhizome Sodium Rhizome, plant
Car-3-Ene Leaf Sodium-Curcumate Plant
Carbohydrates Rhizome Starch Rhizome
Caryophyllene Essential oil, rhizome, tuber Stigmasterol Rhizome, root
Cholesterol Rhizome Sugars Plant
Chromium Plant, rhizome Syringic-Acid Leaf
Cineol Rhizome essential oil, rhizome, tuber Terpinene Rhizome essential oil, essential oil, rhizome, tuber
Cineole Essential oil Terpineol Essential oil, rhizome essential oil
Cinnamic-Acid Rhizome Terpinolene Leaf
Cobalt Plant, rhizome Tetrahydrocurcumin Plant
Copper Rhizome Thiamin Rhizome
Cuminyl-Alcohol Rhizome Thiamine Plant
Curcumene Essential oil, rhizome essential oil, rhizome, tuber Tolyl-Methylcarbinol Rhizome
Curcumenol Rhizome essential oil, essential oil, rhizome Triethylcurcumin Plant
Curcumenone Rhizome Turmerin Rhizome
Curcumin Resin, exudate, sap, rhizome, plant, root Turmerone Rhizome, rhizome essential oil, root
Curcuminoids Root Turmeronol-A Rhizome
Curcumol Rhizome Turmeronol-B Rhizome
Curdione Essential oil, rhizome, tuber, rhizome essential oil Ukonan-A Rhizome
Curlone Rhizome Ukonan-B Rhizome
Curzerenone Rhizome, tuber Ukonan-C Rhizome
Curzerenone-C Essential oil, rhizome essential oil Ukonan-D Rhizome
Cyclo-Isoprenemyrcene Rhizome Unsaturated-Fatty-Acids Rhizome
Cyclocurcumin Rhizome Vanillic-Acid Leaf
D-Alpha-Phellandrene Rhizome Zedoarondiol Rhizome
D-Camphene Rhizome Zinc Plant rhizome
D-Camphor Rhizome Zingiberene Rhizome root, rhizome essential oil


Table 2: Molecular docking results of all the phytocompounds from Curcuma longa along with the reference molecules (Hydroxychloroquine)
Lowest binding
Lowest binding
Phytocompounds
Pubchem Id
energy (kcal mol1)
Phytocompounds
Pubchem Id
energy (kcal mol1)
Beta-Carotene
5280489
-10.12
Syringic-Acid
10742
-6.91
Beta-Sitosterol
222284
-9.96
1,7-Bis-(4-Hydroxyphenyl)-1-Heptene-3,5-Dione
9796708
-6.87
Stigmasterol
5280794
-9.94
Turmeronol-A
15858385
-6.87
Campesterol
173183
-9.72
Protocatechuic-Acid
72
-6.86
Cholesterol
5997
-9.65
Alpha-Curcumene
92139
-6.85
Phytosterols
12303662
-9.61
Germacrone
6436348
-6.82
Ascorbic-Acid
54670067
-9.02
Alpha-Terpineol
17100
-6.8
Cyclocurcumin
69879809
-9.01
O-Coumaric-Acid
323
-6.79
Quercetin
5280343
-8.84
P-Coumaric-Acid
637542
-6.75
Demethoxycurcumin
5469424
-8.57
Caryophyllene
5281515
-6.63
Riboflavin
493570
-8.54
Bisacumol
5315469
-6.61
Dicinnamoylmethane
390472
-8.53
Cinnamic-Acid
444539
-6.61
Bisacurone
14287397
-8.31
P-Methoxy-Cinnamic-Acid
13245
-6.58
Calebin-A
637429
-8.05
Tetrahydrocurcumin
124072
-6.56
Dihydrocurcumin
10429233
-7.96
Camphor
2537
-6.46
Curcumenone
153845
-7.68
D-Camphor
159055
-6.46
Isoprocurcumenol
14543198
-7.59
Borneol/Isoborneol
64685
-6.45
Curcumenol
167812
-7.57
Beta-Pinene
14896
-6.34
Beta-Turmerone
196216
-7.55
Curzerenone
3081930
-6.33
Bis-Demethoxycurcumin
5315472
-7.52
D-Sabinene
10887971
-6.24
Alpha-Tocopherol
14985
-7.47
Niacin
938
-6.19
Zedoarondiol
24834047
-7.42
Alpha-Phellandrene
7460
-6.12
Beta-Sesquiphellandrene
12315492
-7.39
Alpha-Pinene
6654
-6.12
Caffeic-Acid
689043
-7.38
Alpha-Terpinene
7462
-6.06
Alpha-Turmerone
14632996
-7.37
Camphene
6616
-6.04
Procurcumenol
189061
-7.26
Caprylic-Acid
379
-6.02
Dehydrocurdione
6442617
-7.24
Limonene
22311
-5.98
Alpha-Atlantone
12299867
-7.21
Eugenol
3314
-5.93
Zingiberene
92776
-7.21
1,8-Cineole
2758
-5.9
Ar-Turmerone
160512
-7.2
D-Camphene
92221
-5.89
Guaiane
9548703
-7.19
Turmerone
14367555
-5.84
Curcumol
14240392
-7.17
Tolyl-Methylcarbinol
110953
-5.77
Curcumin
969516
-7.16
Arabinose
439195
-5.76
Bisabola-3,10-Dien-2-One
10421034
-7.15
Thiamin
1130
-5.70
Beta-Bisabolene
10104370
-7.14
Car-3-Ene
26049
-5.68
Curdione
6441391
-7.13
Linalol
6549
-5.66
Bisabolene
3033866
-7.12
Terpinolene
11463
-5.66
Epi-Procurcumenol
10263440
-7.1
Cuminyl-Alcohol
325
-5.62
Germacrene
9548705
-7.08
P-Cymene
7463
-5.62
1-Hydroxy-1,7-Bis-(4-Hydroxy-3-Methoxyphenyl)-6-Heptene-3,5-Dione
68548065
-7.05
Azulene
9231
-5.61
Gamma-Atlantone
91698329
-7.04
Gamma-Terpinene
7461
-5.41
Vanillic-Acid
8468
-6.98
Guaiacol
460
-5.37
Turmeronol-B
10955433
-6.94
Hydroxy Chloroquine
3652
-7.23


Image for - Investigation on the Impact of Potential Phytocompounds from Curcuma longa Against COVID-19
Fig. 1(a-t): Molecular docking of the active compounds from Curcuma longa to the amino acid residues of main protease (PDB ID: 6Y84), (a) Beta-carotene, (b) Beta-sitosterol, (c) Stigmasterol, (d) Campesterol, (e) Cholesterol, (f) Phytosterols, (g) Ascorbic-acid, (h) Cyclocurcumin, (i) Quercetin, (j) Demethoxycurcumin, (k) Riboflavin, (l) Dicinnamoylmethane (m) Bisacurone, (n) Calebin-A, (o) Dihydrocurcumin, (p) Curcumenone, (q) Isoprocurcumenol, (r) Curcumenol, (s) Beta-turmerone and (t) Bis-demethoxycurcumin

The UniProt ID of PODTD1 showed more than 75 crystal structures of SARS-CoV-2 Mpro. The 6Y84 was the crystallized structure with an unliganded active site.

Molecular docking analysis: The virtual screening of all the 85 compounds as well as the reference molecule (Hydroxychloroquine) was done against the receptor protein (SARS-CoV-2 Mpro 6Y84). The compounds with a binding energy of less than -7.5 kcal mol–1 were considered as highly active compounds. Among the tested 85 compounds and 20 compounds such as Beta-Carotene, Beta-Sitosterol, Stigmasterol, Campesterol, Cholesterol, Phytosterols, Ascorbic-Acid, Cyclocurcumin, Quercetin, Demeth-oxycurcumin, Riboflavin, Dicinnamoylmethane, Bisacurone, Calebin-A, Dihydrocurcumin, Curcumenone, Isopro-curcumenol, Curcumenol, Beta-Turmerone, Bis-Demethoxycurcumin were showed the binding energy of less than -7.5 kcal mol1 which were considered as active compounds (Table 2). The molecular docking data of the active 20 compounds were given in Fig. 1a-t (a) Beta-Carotene, (b) Beta-Sitosterol, (c) Stigmasterol, (d) Campesterol, (e) Cholesterol, (f) Phytosterols, (g) Ascorbic-Acid, (h) Cyclocurcumin, (i) Quercetin, (j) Demethoxycurcumin, (k) Riboflavin, (l) Dicinnamoylmethane (m) Bisacurone, (n) Calebin-A, (o) Dihydrocurcumin, (p) Curcumenone, (q) Isoprocurcumenol, (r) Curcumenol, (s) Beta-Turmerone, (t) Bis-Demethoxycurcumin and the reference molecule (Hydroxychloroquine) was given in Fig. 2a. Among the docked 85 compounds and 20 compounds showed the binding energy in the range of -10.12-7.52 kcal mol1. The Hydroxychloroquine (reference molecule) has shown the binding energy of -7.23 kcal mol1 which was lesser than the binding energy of 30 compounds from Curcuma longa. The 20 compounds from Curcuma longa showed a binding energy of less than -7.5 kcal mol1 which were considered as highly active compounds against SARS-CoV-2. The seven compounds such as Alpha-Tocopherol, Zedoarondiol, Beta-Sesquiphellandrene, Caffeic-Acid, Alpha-Turmerone, Procurcumenol, Dehydrocurdione were also showing the binding energy in the range of -7.47 to -7.24 kcal mol1 which was lesser than the reference molecule hydroxychloroquine (Table 2).

Among the 20 compounds, Beta-Carotene was showing the highest activity with the binding energy of -10.12 kcal mol1 and the other compounds such as Beta-Sitosterol, Stigmasterol, Campesterol, Cholesterol, Phytosterols, Ascorbic-Acid and Cyclocurcumin were displaying the binding energy between -9.96 to -9.01 kcal mol1. The compounds such as Quercetin, Demetho-xycurcumin, Riboflavin, Di-Cinnamoyl Methane, Bisacurone, Calebin-A, Dihydrocurcumin, Curcumenone, Isopro-curcumenol, Curcumenol, Beta-Turmerone and Bisdemetho-xycurcumin were showing the binding energy between -8.84 to -7.52 kcal mol1. Most of these active compounds were present in the rhizome of the Curcuma longa (Table 1).

Among these compounds, ascorbic acid (vitamin C) was studied by the Zhongnan Hospital (NCT04264533) to check its clinical efficacy against COVID-19. Quite a few studies have proved that ascorbic acid can be used to treat severe viral respiratory tract infections and SARS-associated viral diseases38 by boosting the immune system. Germacrone was one of the principal components of Curcuma longa rhizome essential oil which can inhibit the growth of pseudorabies and Influenza viruses39,40. In this study, it was observed that the germacrone is having less activity (-6.82) against SARS-CoV-2.

Image for - Investigation on the Impact of Potential Phytocompounds from Curcuma longa Against COVID-19
Fig. 2(a-b): (a) Molecular docking and (b) Interactions of hydroxychloroquine (reference molecule) with the amino acid residues of the main protease

Several researchers have suggested that the curcumin from Curcuma longa could be used as a potential drug to treat COVID-19 patients41,33. But this study proved that 32 compounds (Table 2) from Curcuma longa had more activity than the curcumin (-7.16). The activity of curcumin was lesser than the activity of Hydroxychloroquine (-7.23 kcal mol1). It was also observed that the active compounds such as Bis-Demethoxycurcumin, Cyclocurcumin, Demethoxycurcumin, Dihydrocurcumin, Tetrahydrocurcumin are the derivatives/metabolites of curcumin42. Curcumin, Bisdemethoxycurcumin and Demethoxycurcumin are the Curcuminoids produced by Curcuminoid synthase43-45 which are responsible for all the pharmacological activities of Curcuma longa46-48. Moreover, Chakraborty et al.49 proved that cyclocurcumin have higher neuronal protection activity than curcumin.

Interaction analysis: The structure of the SARS-CoV-2 Mpro 6Y84 protein was considered a rigid molecule and the phytocompounds of Curcuma longa were considered as flexible molecules during the docking analysis. From the docking, it was found that the 20 compounds from Curcuma longa were highly active against SARS-CoV-2. All the active 20 compounds and the reference molecule (Hydroxychloroquine) were subjected to interaction analysis by a protein-ligand interaction profiler. The interaction analysis showed that all the active compounds and the reference molecule (Hydroxychloroquine) were interacted with the amino acid residues of SARS-CoV-2 Mpro by forming hydrogen bonds as well as hydrophobic interactions except Beta-Carotene (Fig. 2b and 3a-t). The LYS5 and TYR126 amino acid residues of SARS-CoV-2 Mpro were commonly interacted by all the active compounds against SARS-CoV-2 except Beta-Carotene (Table 3, 4).

The Beta-Carotene interacted with the target protein through nine hydrophobic interactions. The compounds such as Riboflavin and Dihydrocurcumin were also showed the TT-cation interaction in the LYS5 residue of protein (Table 5). The LYS5 residue was also involved in other kinds of interactions such as hydrophobic and hydrogen bond interactions (Table 3, 4). The hydroxychloroquine was showing three hydrophobic interactions with the amino acid residues such as LYS5 and TYR126 while the other tested molecules from Curcuma longa was showing a higher number of hydrophobic interactions except for riboflavin which was showing two i.e., LYS5 and TYR126. The TYR126 hydrophobic interaction was displayed by all the active molecules of Curcuma longa except Bis-Demethoxycurcumin. The LYS5 hydrophobic interaction was also observed in all the active molecules except Beta-Carotene.

Hydroxychloroquine is interacting with the protein by six hydrogen bond interactions with three amino acid residues such as LYS5, ARG4 and GLN127 (Fig. 2b). The Beta-Carotene was not showing any hydrogen bond interaction while all other active compounds were showing the hydrogen bond interactions. The LYS5 residue of the SARS-CoV-2 Mpro interacted through hydrogen bond interaction with all the active compounds except Isoprocurcumenol, Campesterol and Beta-Sitosterol. ARG4 residue of the SARS-CoV-2 Mpro was interacted by the compounds such as Stigmasterol, Cholesterol and Curcumenone through hydrogen bond interaction. The six active compounds such as Quercetin, Riboflavin, Bisacurone, Calebin-A, Dihydrocurcumin and Isoprocurcumenol interacted through hydrogen bond interaction with the GLN127 residue. LYS137 residue was interacted by the active molecules such as Campesterol, Cyclocurcumin, Quercetin, Demethoxycurcumin, Riboflavin and Bisacurone through hydrogen bond interaction (Table 4).

The common interaction analysis between the five best active compounds (Beta-Carotene, Beta-Sitosterol, Stigmasterol, Campesterol and Cholesterol) and the SARS-CoV-2 Mpro was done with the help of Ligplot+ v.1.4.5 software. It was observed that the amino acid residues such as TYR126, LYS137, GLY138 and Ser139 interacted with all the five best active compounds (Fig. 4). The common interaction analysis between the Beta-Carotene and Hydroxychloroquine showed that the TYR126, LYS137 and GLU290 amino acid residues were involved in a common interaction (Fig. 5). These results confirmed that the amino acids residues of SARS-CoV-2 Mpro were affected by the active compounds of Curcuma longa.

Drug-likeness properties: The ADME profiles of all the active phytocompounds of Curcuma longa and hydroxychloroquine was displayed in Table 6. The molecular weight of all the active compounds of Curcuma longa was under 500 and the bioavailability score was 0.55/0.56 except Beta-Carotene. All the active phytocompounds of Curcuma longa were agreeing with Lipinski’s rule of 5 except Beta-Carotene. Even though the Beta-Carotene was the highest active compound (-10.12 kcal mol1 of binding energy) in Curcuma longa against SARS-CoV-2, it could not be used as a drug for the treatment of COVID-19 because it is not obeying Lipinski’s rule of 5. But some studies proved that Beta-Carotene is not showing any cytotoxic effect against normal and cancer cells50,51. The interaction between the Beta-Carotene and casein in milk was necessary for the stable conformation of casein52. The Beta-Carotene is also rich in pigmented fruits and vegetables (orange and carrot) and is responsible for their biological activities and colour53-55.

Image for - Investigation on the Impact of Potential Phytocompounds from Curcuma longa Against COVID-19
Fig. 3(a-t):
Interactions of the active compounds from Curcuma longa with the amino acid residues of the main protease, (a) Beta-carotene, (b) Beta-sitosterol, (c) Stigmasterol, (d) Campesterol, (e) Cholesterol, (f) Phytosterols, (g) Ascorbic-acid, (h) Cyclocurcumin, (i) Quercetin, (j) Demethoxycurcumin, (k) Riboflavin, (l) Dicinnamoylmethane, (m) Bisacurone, (n) Calebin-a, (o) Dihydrocurcumin, (p) Curcumenone, (q) Isoprocurcumenol, (r) Curcumenol, (s) Beta-turmerone and (t) Bis-demethoxycurcumin


Table 3: Interaction analysis data of active phytocompounds from Curcuma longa (hydrophobic interaction)
Compounds
Lowest binding energy (kcal mol1)
Number of hydrophobic interactions
Residue
AA
Distance
Ligand atom
Protein atom
Beta-Carotene
-10.12
9
125
VAL
3.96
3098
1281
126
TYR
3.40
3117
1291
126
TYR
3.39
3119
1289
126
TYR
3.22
3122
1292
137
LYS
3.99
3129
1424
137
LYS
3.71
3124
1420
137
LYS
3.77
3127
1428
137
LYS
3.31
3132
1425
137
LYS
3.13
3131
1429
Beta-Sitosterol
-9.96
6
5A
LYS
3.21
3097
70
126
TYR
3.93
3116
1288
126
TYR
3.40
3117
1290
288
GLU
3.94
3107
2921
288
GLU
3.83
3111
2920
291
PHE
3.30
3111
2956
Stigmasterol
-9.94
9
5A
LYS
3.03
3107
69
5A
LYS
3.91
3108
71
5A
LYS
3.62
3097
72
126
TYR
3.44
3104
1288
126
TYR
3.91
3101
1290
137
LYS
3.54
3121
1420
137
LYS
3.42
3115
1425
137
LYS
3.20
3118
1424
137
LYS
3.39
3114
1429
Campesterol
-9.72
5
5
LYS
3.57
3098
69
5
LYS
3.49
3099
71
126
TYR
3.57
3099
1288
127
GLN
3.86
3099
1308
137
LYS
4.000
3111
1425
Cholesterol
-9.65
9
5
LYS
3.06
3107
69
5
LYS
3.53
3097
72
5
LYS
3.83
3104
71
126
TYR
3.59
3104
1288
126
TYR
3.70
3101
1290
137
LYS
3.31
3115
1425
137
LYS
3.14
3118
1424
137
LYS
3.58
3119
1418
137
LYS
3.47
3114
1429
Phytosterols
-9.61
4
5
LYS
3.23
3097
70
126
TYR
3.58
3122
1290
288
GLU
3.36
3111
2920
291
PHE
3.53
3111
2956
Ascorbic-Acid
-9.02
4
5
LYS
3.56
3125
70
137
LYS
3.41
3108
1420
288
GLU
3.61
3138
2920
291
PHE
3.46
3138
2956
Cyclocurcumin
-9.01
7
5
LYS
3.22
3102
71
5
LYS
3.43
3100
72
7
ALA
3.34
3107
98
126
TYR
3.51
3101
1288
127
GLN
3.76
3108
1307
127
GLN
3.83
3102
1308
137
LYS
3.90
3114
1420
Quercetin
-8.84
3
5
LYS
3.54
3106
72
126
TYR
3.87
3102
1288
126
TYR
3.67
3110
1290
Demethoxycurcumin
-8.57
6
5
LYS
3.43
3115
69
5
LYS
3.98
3116
71
126
TYR
3.41
3110
1288
128
CYS
3.82
3099
1331
137
LYS
3.28
3106
1429
290
GLU
3.45
3103
2942
Riboflavin
-8.54
2
5
LYS
3.22
3106
69
126
TYR
3.43
3109
1288
Dicinnamoylmethane
-8.53
9
5
LYS
3.40
3108
70
5
LYS
3.19
3098
71
5
LYS
3.78
3114
75
7
ALA
3.53
3101
98
126
TYR
3.80
3099
1288
127
GLN
3.94
3100
1307
288
GLU
3.43
3113
2920
291
PHE
3.87
3111
2957
291
PHE
3.26
3113
2956
Bisacurone
-8.31
3
5
LYS
3.94
3106
71
126
TYR
3.57
3102
1289
128
CYS
3.86
3095
1331
Calebin-A
-8.05
6
5
LYS
3.33
3098
72
126
TYR
3.85
3112
1288
126
TYR
3.74
3113
1289
128
CYS
4.00
3105
1331
137
LYS
3.57
3118
1420
137
LYS
3.82
3104
1425
Dihydrocurcumin
-7.96
5
5
LYS
3.51
3117
69
5
LYS
3.98
3118
72
5
LYS
3.66
3114
71
126
TYR
3.51
3114
1288
137
LYS
3.86
3104
1420
Curcumenone
-7.68
3
5
LYS
3.37
3105
70
5
LYS
3.30
3107
71
126
TYR
3.95
3107
1288
Isoprocurcumenol
-7.59
4
5
LYS
3.36
3102
72
126
TYR
3.18
3099
1288
126
TYR
3.81
3104
1290
137
LYS
3.90
3109
1425
Curcumenol
-7.57
5
5
LYS
3.29
3105
71
126
TYR
3.07
3099
1288
126
TYR
3.77
3107
1290
137
LYS
3.90
3107
1420
290
GLU
3.74
3108
2942
Beta-Turmerone
-7.55
6
5
LYS
3.52
3109
69
5
LYS
3.16
3106
71
126
TYR
3.94
3108
1288
126
TYR
3.22
3102
1290
127
GLN
3.90
3106
1308
137
LYS
3.65
3098
1420
Bis-Demethoxycurcumin
-7.52
4
5
LYS
3.45
3094
71
7
ALA
3.24
3101
98
137
LYS
3.64
3115
1420
137
LYS
3.43
3113
1425
Hydroxchloroquine
-7.23
3
5
LYS
3.51
3098
71
5
LYS
3.76
3097
72
126
TYR
3.31
3099
1288


Table 4: Interaction analysis data of active phytocompounds from Curcuma longa (hydrogen bond interaction)
Compounds
Number of hydrogen bonds
Residue
AA
Distance H-A
Distance D-A
Donor Angle
Donor atom
Acceptor atom
Beta-Carotene
0
-
-
-
-
-
-
-
Beta-Sitosterol
2
207
TRP
2.62
3.50
144.09
2080 [Nar]
3123 [O3]
282
LEU
2.18
3.13
163.24
3123 [O3]
2859 [O2]
Stigmasterol
2
4
ARG
3.07
3.85
133.98
53 [Ng+]
3123 [O3]
5
LYS
2.69
3.24
115.86
3123 [O3]
67 [O3]
Campesterol
2
137
LYS
3.53
4.04
115.5
1423 [O3]
3122 [O3]
290
GLU
2.94
3.82
152.44
3122 [O3]
2945 [O3]
Cholesterol
2
4
ARG
2.35
3.16
135.66
53 [Ng+]
3121 [O3]
5
LYS
3.15
3.62
111.07
3121 [O3]
67 [O3]
Phytosterols
2
207
TRP
2.21
3.16
154.59
2080 [Nar]
3123 [O3]
282
LEU
1.95
2.88
159.22
3123 [O3]
2859 [O2]
Ascorbic-Acid
2
5
LYS
3.27
4.01
132.21
59 [N3]
3132 [O3]
5
LYS
2.72
3.53
140.77
77 [N3]
3119 [O3]
Cyclocurcumin
2
5
LYS
1.8
2.55
129.93
77 [N3]
3095 [O2]
137
LYS
3.38
3.91
116.37
1423 [O3]
3119 [O3]
Quercetin
8
5
LYS
2.11
2.89
134.61
77 [N3]
3111 [O3]
5
LYS
2.22
2.92
124.43
81 [N3]
3111 [O3]
7
ALA
2.45
3.20
129.64
93 [Nam]
3119 [O3]
125
VAL
2.99
3.83
145.18
3119 [O3]
1279 [O2]
127
GLN
2.04
3.04
164.28
1297 [N3]
3094 [O2]
127
GLN
2.00
3.02
173.6
1299 [N3]
3094 [O2]
137
LYS
1.94
2.86
156.17
3113 [O3]
1422 [O2]
290
GLU
1.62
2.49
147.36
3111 [O3]
2944 [O2]
Demethoxycurcumin
5
5
LYS
3.38
3.90
114.48
59 [N3]
3119 [O3]
5
LYS
3.23
3.90
124.74
61 [N3]
3119 [O3]
5
LYS
1.96
2.81
144.29
3119 [O3]
67 [O3]
137
LYS
1.94
2.87
161.49
1423 [O3]
3098 [O2]
289
ASP
1.87
2.75
148.23
3107 [O3]
2934 [O2]
Riboflavin
8
5
LYS
3.15
4.03
150.69
77 [N3]
3097 [N2]
5
LYS
2.44
3.13
124.39
81 [N3]
3115 [O3]
127
GLN
2.02
2.94
158.09
3115 [O3]
1306 [O3]
137
LYS
2.55
3.11
116.79
1423 [O3]
3124 [O3]
137
LYS
2.21
2.90
126.91
3121 [O3]
1423 [O3]
138
GLY
3.14
3.49
102.97
3124 [O3]
1443 [O2]
288
GLU
1.70
2.65
154.32
3099 [Nam]
2926 [O2]
290
GLU
2.51
3.12
120.52
3118 [O3]
2944 [O2]
Dicinnamoylmethane
2
5
LYS
2.12
2.97
140.09
81 [N3]
3096 [O2]
5
LYS
2.35
2.91
115.55
77 [N3]
3096 [O2]
Bisacurone
6
5
LYS
1.76
2.69
150.55
81 [N3]
3112 [O3]
5
LYS
1.79
2.65
145.11
77 [N3]
3112 [O3]
127
GLN
2.03
2.94
148.01
1299 [N3]
3105 [O2]
127
GLN
2.15
3.01
140.32
1297 [N3]
3105 [O2]
137
LYS
1.75
2.67
156.77
3110 [O3]
1423 [O3]
290
GLU
1.84
2.61
134.36
3112 [O3]
2944 [O2]
Calebin-A
5
5
LYS
2.78
3.30
113.72
81 [N3]
3106 [O3]
5
LYS
2.84
3.29
107.59
77 [N3]
3106 [O3]
127
GLN
2.00
3.00
167.19
1299 [N3]
3097 [O2]
127
GLN
1.96
2.98
175.52
1297 [N3]
3097 [O2]
290
GLU
2.03
2.99
167.39
3108 [O3]
2945 [O3]
Dihydrocurcumin
7
5
LYS
3.71
4.10
105.54
59 [N3]
3121 [O3]
5
LYS
3.14
4.09
156.87
61 [N3]
3121 [O3]
5
LYS
1.74
2.55
138.2
3121 [O3]
68 [O3]
127
GLN
2.59
3.45
141.41
1299 [N3]
3119 [O3]
127
GLN
2.46
3.37
148.73
1297 [N3]
3119 [O3]
170
GLY
2.04
2.91
146.76
3107 [O3]
1741 [O2]
172
HIS
3.20
3.55
101.92
1761 [Npl]
3107 [O3]
Curcumenone
4
4
ARG
2.20
3.15
154.59
53 [Ng+]
3094 [O2]
5
LYS
2.05
3.04
171.47
59 [N3]
3094 [O2]
5
LYS
2.51
3.06
113.45
61 [N3]
3094 [O2]
5
LYS
2.09
2.91
139.64
77 [N3]
3109 [O2]
Isoprocurcumenol
3
127
GLN
1.90
2.85
152.72
1297 [N3]
3110 [O3]
127
GLN
1.84
2.82
159.76
1299 [N3]
3110 [O3]
127
GLN
2.05
3.02
172.76
3110 [O3]
1305 [O3]
Curcumenol
2
5
LYS
1.77
2.70
157.46
77 [N3]
3110 [O3]
290
GLU
1.84
2.53
125.32
3110 [O3]
2944 [O2]
Beta-Turmerone
2
5
LYS
2.09
2.97
142.64
81 [N3]
3105 [O2]
5
LYS
2.03
2.91
150.18
77 [N3]
3105 [O2]
Bis-Demethoxycurcumin
2
5
LYS
1.69
2.66
156.79
81 [N3]
3108 [O2]
5
LYS
2.09
2.60
110.52
77 [N3]
3108 [O2]
Hydroxchloroquine
6
4
ARG
2.43
3.43
167.09
53 [Ng+]
3112 [Nar]
5
LYS
1.90
2.87
160.98
59 [N3]
3112 [Nar]
5
LYS
2.12
2.88
129.46
61 [N3]
3112 [Nar]
5
LYS
1.84
2.77
150.45
81 [N3]
3104 [O3]
5
LYS
1.97
2.71
130.62
77 [N3]
3104 [O3]
127
GLN
1.66
2.52
144.23
3104 [O3]
1305 [O3]


Table 5: Interaction analysis data of active phytocompounds from Curcuma longa (TT-cation interaction)
Compounds
Number of interactions
Residue
AA
Distance
Offset
Ligand groups
Ligand atoms
Riboflavin
2
5
LYS
3.7
1.23
Aromatic
3096, 3097, 3100, 3101, 3102, 3104
5
LYS
3.7
1.22
Aromatic
3098, 3099, 3101, 3104, 3108, 3111
Dihydrocurcumin
1
5
LYS
4.88
1.81
Aromatic
3113, 3114, 3115, 3116, 3117, 3118


Table 6: ADME properties of the active phytochemicals from Curcuma longa and Hydroxychloroquine
Molecular weight
Number of
Molar
TPSA
Concensus
Bioavailability
GI
BBA
Synthetic
Compounds
(g mol1)
rotatable bonds
refractivity
(Å2)
log P
Log S
Lipinski
Ghose
Veber
Egan
Muegge
score
Absorption
permeant
accessibility (SA)
Beta-Carotene
536.87
10
184.43
0.00
11.13
-11.04
No
No
Yes
No
No
0.17
Low
No
6.19
Beta-Sitosterol
414.71
6
133.23
20.23
7.24
-7.90
Yes
No
Yes
No
No
0.55
Low
No
6.3
Stigmasterol
412.69
5
132.75
20.23
6.98
-7.46
Yes
No
Yes
No
No
0.55
Low
No
6.21
Campesterol
400.68
5
128.42
20.23
6.92
-7.54
Yes
No
Yes
No
No
0.55
Low
No
6.17
Cholesterol
386.65
5
123.61
20.23
6.75
-7.40
Yes
No
Yes
No
No
0.55
Low
No
5.98
Phytosterols
414.71
6
133.23
20.23
7.24
-7.90
Yes
No
Yes
No
No
0.55
Low
No
6.3
Ascorbic-Acid
176.12
2
35.12
107.22
-1.42
0.23
Yes
No
Yes
Yes
No
0.56
High
No
3.47
Cyclocurcumin
368.38
5
100.78
85.22
2.82
-4.01
Yes
Yes
Yes
Yes
Yes
0.56
High
No
4.21
Quercetin
302.24
1
78.04
131.36
1.23
-3.16
Yes
Yes
Yes
Yes
Yes
0.55
High
No
3.23
Demethoxycurcumin
338.35
7
96.31
83.83
3.00
-3.92
Yes
Yes
Yes
Yes
Yes
0.55
High
No
2.82
Riboflavin
376.36
5
96.99
161.56
-0.19
-1.31
Yes
No
No
No
No
0.55
Low
No
3.84
Dicinnamoylmethane
276.33
6
85.77
34.14
3.71
-4.08
Yes
Yes
Yes
Yes
Yes
0.55
High
Yes
2.68
Bisacurone
252.35
4
73.73
57.53
2.16
-2.32
Yes
Yes
Yes
Yes
Yes
0.55
High
Yes
4.39
Calebin-A
384.38
9
103.89
102.29
2.88
-4.01
Yes
Yes
Yes
Yes
Yes
0.55
High
No
3.24
Dihydrocurcumin
370.4
9
102.48
93.06
2.97
-3.77
Yes
Yes
Yes
Yes
Yes
0.55
High
No
3.1
Curcumenone
234.33
3
69.66
34.14
2.97
-2.61
Yes
Yes
Yes
Yes
Yes
0.55
High
Yes
3.66
Isoprocurcumenol
234.33
0
70.44
37.30
2.75
-2.72
Yes
Yes
Yes
Yes
Yes
0.55
High
Yes
3.89
Curcumenol
234.33
0
69.25
29.46
2.91
-2.70
Yes
Yes
Yes
Yes
Yes
0.55
High
Yes
5.73
Beta-Turmerone
218.33
4
70.88
17.07
3.69
-3.46
Yes
Yes
Yes
Yes
No
0.55
High
Yes
4.17
Bis-Demethoxycurcumin
308.33
6
89.82
74.60
2.83
-3.80
Yes
Yes
Yes
Yes
Yes
0.55
High
Yes
2.59
Hydroxchloroquine
335.87
9
98.57
48.39
3.29
-3.91
Yes
Yes
Yes
Yes
Yes
0.55
High
Yes
2.82


Image for - Investigation on the Impact of Potential Phytocompounds from Curcuma longa Against COVID-19
Fig. 4: Common interaction between the five active compounds from Curcuma longa
Rounded amino acids indicated the common interaction, five active compounds (beta-carotene, beta-sitosterol, stigmasterol, campesterol, cholesterol)


Table 7: Pharmacophore features of the active phytochemicals from Curcuma longa and Hydroxychloroquine
Molecules
Atoms
Features
Spatial features
Aromatic
Hydrophobic
Donors
Acceptors
Negatives
Positives
Beta-carotene
96
51
32
0
51
0
0
0
0
Beta-sitosterol
80
38
31
0
36
1
1
0
0
Phytosterols
80
38
31
0
36
1
1
0
0
Stigmasterol
78
38
31
0
36
1
1
0
0
Campesterol
77
37
31
0
35
1
1
0
0
Cholesterol
74
35
31
0
33
1
1
0
0
Riboflavin
48
21
17
3
4
6
7
0
1
Bisacurone
42
16
14
0
11
2
3
0
0
Beta-turmerone
38
15
15
0
14
0
1
0
0
Calebina
48
15
13
2
4
2
7
0
0
Curcumenol
39
15
14
0
12
1
2
0
0
Curcumenone
39
15
15
0
13
0
2
0
0
Dihydrocurcumin
49
15
13
2
5
2
6
0
0
Quercetin
32
15
10
3
0
5
7
0
0
Cyclocurcumin
47
14
12
2
4
2
6
0
0
Isoprocurcumenol
39
14
13
0
11
1
2
0
0
Demethoxycurcumin
43
12
10
2
3
2
5
0
0
Ascorbic acid
20
10
6
0
0
4
6
0
0
Bisdemethoxycurcumin
39
10
8
2
2
2
4
0
0
Dicinnamoylmethane
37
6
6
2
2
0
2
0
0
Hydroxychloroquine
49
10
9
2
3
2
3
0
0


Image for - Investigation on the Impact of Potential Phytocompounds from Curcuma longa Against COVID-19
Fig. 5: Common interaction between the hydroxychloroquine and beta-carotene
Rounded amino acids indicated the common interaction

In Curcuma longa also the Beta-Carotene is contributing to its biological activities. So, Beta-Carotene rich fruits and vegetables can be recommended as the natural remedy for COVID-19 patients. The other 19 molecules Curcuma longa are obey Lipinski’s rule of 5. So, they can be used as drug candidates against COVID-19 with clinical trials.

Pharmacophore study: PharmaGist webserver was used to identify the important special and structural features of active phytochemicals from Curcuma longa. Pharmacophore features in the screened active phytochemicals were represented by a set of special and structural features which were responsible for their biological activity in the active site of the target protein (Table 7). These pharmacophore features are helpful for the interaction with the target proteins. The normal pharmacophore of a compound is consisting of aromatic, hydrophobic elements, hydrogen bonds donors and acceptors, positive and negative functional groups56. Among the active phytochemicals, Beta-Carotene is having the highest number of structural and special features which may be responsible for the highest binding activity (-10.12 kcal mol1). The number of donors and acceptors present in the molecules were not responsible for the binding activity because Beta-Carotene did not have any donors or acceptors whereas the riboflavin is having 6 donors and 7 acceptors.

The pharmacophoric features of the 20 active compounds were compared with the reference compound (Hydroxychloroquine). The pharmacophore analysis revealed that all the active 20 compounds from Curcuma longa have essential features comparable to the reference molecule. So, they can be used as a drug candidate against SARS-CoV-2. Besides, ADME results revealed that all the active compounds are non-toxic to humans except Beta-Carotene. All the 20 active compounds were present in the rhizome of the Curcuma longa (Table 1). Numerous studies have reported that the rhizome of Curcuma longa was used as herbal medicine to treat a wide variety of viral diseases57. The present study also proved that the rhizome was having all the active substances against SARS-CoV-2. So, the Curcuma longa rhizome itself can be recommended as herbal medicine against COVID-19. The findings of this study are preliminary and further molecular dynamics and simulation studies are required for more precise confirmations. The dose-dependent activity of Curcuma longa against COVID-19 should be carried out to get a deeper insight into the mode of inhibition.

CONCLUSION

The results of this study proved that twenty active compounds from Curcuma longa were capable to bind to the main protease of SARS-CoV2. The phytochemicals such as Beta-Carotene, Beta-Sitosterol, Stigmasterol, Campesterol, Cholesterol, Phytosterols, Ascorbic-Acid and Cyclocurcumin had remarkably high binding energies and were present in the rhizome of Curcuma longa. So, the rhizome of Curcuma longa is a potential candidate for clinical research against COVID-19.

SIGNIFICANCE STATEMENT

This study discovers the active twenty phytocompounds from Curcuma longa to act against SARS-CoV2. All the twenty active compounds were present in the rhizome of Curcuma longa. It is possible to synergistically act all these compounds against COVID-19. So, the rhizome of Curcuma longa is a potential candidate for clinical research against COVID-19. This study will help the researcher to identify a suitable drug candidate against COVID-19.

ACKNOWLEDGMENTS

The authors wish to thank the management of the Malankara Catholic College and Hindustan Institute of Technology and Science for giving support to this study. The authors also wish to thank Dr. K. Nandakumar (Director, Research, Hindustan Institute of Technology and Science, Chennai), Rev. Fr. Prem Kumar, Rev. Fr. Jose Bright and Mr. K. Suresh for their encouragement in this study.

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