Natural Potential Inhibitors for Covid 19 – An Insilico Approach

 

A. Anto Arockia Raj1*, J. Vinnarasi2

1Department of Chemistry, St. Xavier’s College (Autonomous), Palayamkottai, Tamil Nadu, India – 627002.

2Department of Chemistry, The Standard Fireworks Rajaratnam College for Women (Autonomous),

Sivakasi, Tamil Nadu, India – 626123.

*Corresponding Author E-mail: aanto.chemistry@gmail.com, vinnisky@gmail.com

 

ABSTRACT:

In 2019 severe acute respiratory syndrome (SARS) - associated with coronavirus is a new highly pathogenic human coronaviruses that emerged in china and has quickly spread all over the world. The mortality rate is about 26% globally. This has resulted in an urgent need to identify antiviral drugs that are active against SARS-Covid -19. Several compounds extracted from natural product and herbs exhibit antiviral activity. In the present study, eight compounds from natural products and five antiviral drugs have selected and docked against SARS-CoV-2. Curcuminoid are chief constituent of turmeric, has been used as a food additive and herbal increment due to its potential medicinal behavior. Curcumin has shown better antiviral effect against dengue, hepatitis C, zika and chikungunya viruses earlier. The molecular docking for exploring the binding abilities between naturally obtained known compounds comparable with Oseltamivir, Remdesivir, hydroxychloroquine, Zanamivir and Ribavirin against SARS-CoV-2, whose results may be used to design potential drug to meet out the need of the hour. The results showed that bismethoxycurcumin, demethoxycurcumin and gedunin have comparable high binding pose energies against SARS-CoV-2. We anticipate that these molecules may lead to the design or discovery of new effective actions for SARS-CoV-2.

 

KEYWORDS: Curcuminoid; Gedunin, Oseltamivir, molecular docking, SARS CoV-2.

 

 

1. INTRODUCTION:

Viral diseases have been an extreme health ailment at all times and scientists have constantly tried to find novel antiviral compounds. Viruses are the root cause for several infectious diseases such as the common cold, flu and warts. They also cause daring illnesses such as small pox, HIV/AIDS, Ebola and corona virus disease. Severe acute respiratory syndrome (SARS) has evolved as a new highly communicable human disease with a major impact all over the world in recent times1. An epidemic global SARS have started in southern China, where numerous cases of a typical pneumonia of mysterious etiology were reported at the end of November 2002. The root cause for SARS has been identified as novel Coronaviridae family. The corona viruses are responsible for respiratory and gastrointestinal disorders2–7.

 

After ten years of occurrence of SARS, another pathogen named Middle East respiratory syndrome coronavirus (MERS-CoV), has evolved in Jeddah and Saudi Arabia; it spread towards middle east Europe and North Africa rapidly8-11. The symptoms of both SARS and MERS are very similar but the consequence of the later is even more deadly than SARS12. As of 17 December 2014, 938 people have been infected with MERS and this has led to 343 reported deceased13.

 

A novel coronavirus designated as covid-19 is another human pathogen. This new virus was discovered in 2019, when viral metagenomics was carried out on three broncho alveolar-lavage specimens from Chinese adult patients with unexplained severe pneumonia14. As the WHO reported on April 08, 2020, there were 1353361 confirmed cases of coronavirus and 79235 peoples were deceased worldwide15.

 

Nature has bestowed with many medicines for the well- being of human but isolation and conversion of new drug is a challenging one16,17. Turmeric (Curcuma longa Linn) belongs to Zingiberaceae family and is cultivated in tropical and subtropical regions worldwide and it initiates from India, Southeast Asia and Indonesia. Turmeric has been used in India to maintain oral hygiene 18. In India and China, turmeric plays a vital role as curative medicine for the treatment of liver disorder for many centuries19,20. Turmeric is one of the most standard medicinal herbs, with a wide range of pharmacological activities such as anti-protozoal21, anti-oxidant22, anti-angiogenic23, anti-inflammatory24, anti-venom activities 25, anti-tumor26, anti-malarial27, anti-proliferative28, anti-microbial29, anti-aging30 and anti-viral31 properties. The medicinal behavior of turmeric has been recognized due to the presence of curcuminoids consists of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids have accomplished as potential therapeutic agent to cure metabolic diseases and cancer due to immense number of biological targets and almost no side effects32,33.

 

Neem (Azadirachta indica), is the member of Meliaceae family, generally found in India, Nepal, Bangladesh, and Pakistan. It has abundant biological and pharmacological activities have been reported including antifungal34, antibacterial35, anti-arthritic, hypoglycemic, anti-gastric ulcer, anti-inflammatory, anti-tumor and anti-pyretic activities36–39. The active components in the neem prevent the diseases.

 

Ginger (Zingiber officinale Roscoe) belongs to the Zingiberaceae family and has been frequently used as a spice and traditional herbal medicine extensively40. Ginger root is used to control common diseases, such as cold, nausea, headache and emesis. The phenolic compounds such as gingerols, shogaols and paradols are the chief compounds account for the medicinal effects of ginger41. It has been found to acquire medicinal behaviors, such as anti-oxidant42, anti-cancer43, anti-microbial44 and anti-inflammatory45 activities. Especially, studies revealed that ginger used as a potential agent to prevent and control several diseases, such as obesity46, neurodegenerative diseases47, chemotherapy-induced nausea48, cardiovascular diseases49, diabetes mellitus50 and respiratory disorders51.

 

Piperine is a naturally occurring alkaloid of pepper; it belongs to Piperaceae family. Black pepper was used as a traditional natural medicinal agent in china and India for the treatment and relief of pain, chills, fever, influenza, rheumatism and muscular pains. In tea form, it was also attributed for relieving strep throat, migraine headaches, poor digestion, and even coma52. It was applicable for increasing the flow of saliva, improving the circulation of blood and stimulating appetite53. At recent times piperine has identified as chemopreventive and antioxidant agent. It also has hepatoprotective, anti-inflammatory, immunomodulatory, stimulatory, anti-carcinogenic54, antimicrobial55 and antiulcer activities56. Due to protective action against radiation, before radiotherapy piperine can be applied to cancer patients57.

 

Oseltamivir is an antiviral neuraminidase inhibitor used for the management and prophylaxis of infection with influenza viruses A and B. Oseltamivir strongly inhibits the action of the viral neuraminidase enzyme found on the surface of the virus, which forbids budding from the host cell, viral replication and infection58. Remdesivir was evaluated as a medicine for Ebola virus, but has probable effect over different types of RNA viruses59. In 2017, it was designated as a medicine for SARS-CoV and MERS-CoV60 and it is also being explored as a potential treatment for SARS-CoV2 infections61. Hydroxychloroquine is a type of an aminoquinoline like chloroquine62. It is a chief medication for the treatment of unsophisticated malaria, rheumatoid arthritis, chronic discoid lupus erythematosus, and systemic lupus erythematosus62. Chloroquine and hydroxychloroquine are both being investigated for the treatment of SARS-CoV-263. Zanamivir is an antiviral neuraminidase inhibitor applicable for the treatment of critical illness due to influenza A and B virus64. Ribavirin is an artificial guanosine nucleoside and antiviral agent that hinders the synthesis of viral mRNA. It is a prime medicine for treating hepatitis C and viral hemorrhagic fevers65.

 

FDA has authorized an issue of reserve medication such as hydroxychloroquine and chloroquine to Covid 1965. The current COVID-19 emergency deserves the crucial development of potential drugs to safeguard the people from this drastic communicable disease. The present study aimed to find out the potential drug against the contagious human pathogen SARS CoV-2 is the need of the hour. At recent times molecular modeling and computational based studies is the pleasant tool to identify the potent drug. So, we tried our best to find the effective probable agents against this novel coronavirus from the nature and compare their activity with the standard anti-viral drugs such as oseltamivir, remdesivir, hydroxychloroquine, zanamivir and ribavirin66.

 

2. MATERIALS AND METHODS:

2.1. Data:

In this study, different naturally occurring antiviral small molecules and standard antiviral drugs have been selected. The compounds are chosen for the following principles: (i) the molecules should be identified from traditional medicine; (ii) the molecules should have been studied previously and be easily commercially available. Based on that the compounds such as curcumin (1), demethoxycurcumin (2), Bismethoxycurcumin (3), Nimbin (4), Nimbolide (5), Gedunin (6), Gingerenone (7) and Piperine (8) were selected with their PubChem identifiers tabulated in table 1.

 

Table 1: Information about the selected compounds and antiviral drugs

S. No.

Natural Sources

Compounds

Pub Chem Identifier

Drugs

Drug Bank

Accession Number

1.

Turmeric

Curcumin

969516

Oseltamivir

DB00198

2.

Demethoxycurcumin

5469424

Remdesivir

DB14761

3.

Bisdemethoxycurcumin

5315472

Hydroxychloroquine

DB01611

4.

Neem

Nimbin

108058

Zanamivir

DB00558

5.

Nimbolide

12313376

Ribavirin

DB00811

6.

Gedunin

12004512

 

 

7.

Ginger

Gingerenone

5281775

 

 

8.

Pepper

Piperine

638024

 

 

 

The antiviral drugs such as Oseltamivir (1), Remdesivir (2), Hydroxychloroquine (3), Zanamivir (4) and Ribavirin (5) were selected with their drug bank accession number and tabulated in table 1.

 

2.2 Preparation of structures:

The X-ray crystallography structure of the SARS CoV2 was obtained from the Protein Data Bank under the ID 5RE4 which was solved by Fearon et al. at the resolutions of 1.88 ˚A 67 and prepared for docking. The structure of the selected small molecules and antiviral drugs were drawn using Marvin Sketch software. The structure was cleaned in 3D format and energy was minimized using Marvin sketch software. The resulting structure was then saved in “mdl mol” and “sdf” file formats for molecular docking studies. The structures of the small molecules and drugs are shown in fig.1and 2 respectively.

 

                  

Fig.1 Chemical structures of the selected small molecules

               

     

Fig.2 Chemical structures of the selected antiviral drugs

 

2.3. Molecular Docking:

In the present study, after the preparation of the protein and ligand, molecular docking studies were performed by Argus Lab 4.0.1 to evaluate the interactions. Argus Lab is implemented with shape based search algorithm. Docking has been done using “Argus Dock” exhaustive search docking function of Argus Lab with grid resolution of 0.40 A˚. Docking precision was set to “Regular precision” and “Flexible” ligand docking mode was employed for each docking run. The stability of each docked pose was evaluated using Argus Lab energy calculations 68. The protein opened in Argus Lab software. The water and non-protein molecules in the PDB files were removed. The binding sites are selected and the selected compound also opened in the same window and docks a ligand. Moreover, due to the non- nature of the docking algorithm, 150 possible binding poses were obtained for each molecule.

 

The best docking model was selected according to the lowest AScore calculated by Argus Lab, and the most suitable binding conformation was selected on the basis of hydrogen bond interactions between the ligand and protein near the substrate binding site. The lowest energy poses indicate the highest binding affinity as high energy produces the unstable conformations.

 

3. RESULTS AND DISCUSSION:

The results obtained in molecular docking studies of the selected compounds such as curcumin, demethoxycurcumin and bisdemethoxycurcumin from turmeric, nimbin, nimbolide and gedunin from neem, gingerenone from ginger, piperine from pepper and very important anti- viral drugs such as Oseltamivir, Remdesivir, hydroxychloroquine, Zanamivir and Ribavirin with SARS-CoV-2 obtained from the protein data bank under the ID 5RE4 and prepared for docking simulations using ArgusLab 4.0.1.The least binding pose energy reveals the maximum activity which has been observed by the ranking of poses generated by AScore, a scoring function of ArgusLab and is represented in Table 2. The best fitted binding poses adopted by the small molecules derived from the natural products and the standard anti -viral drugs with SARS-CoV-2 is shown in the fig.3.   


 

Table 2: Binding energies of selected compounds, drugs with SARS-CoV-2

S. No.

Natural Sources

Compounds

A Score (kcal/mol)

Drugs

A Score (kcal/mol)

1.

Turmeric

Curcumin

-9.28784

Oseltamivir

-8.41777

2.

Demethoxycurcumin

-10.4968

Remdesivir

-8.09065

3.

Bisdemethoxycurcumin

-10.5180

Hydroxychloroquine

-8.07116

4.

Neem

Nimbin

-9.93771

Zanamivir

-6.73881

5.

Nimbolide

-8.60309

Ribavirin

-5.34579

6.

Gedunin

-10.0547

 

 

7.

Ginger

Gingerenone

-9.94035

 

 

8.

Pepper

Piperine

-9.56878

 

 

 

Figure 3: Docking of selected compounds and drugs with protein binding sites are shown in cartoon ribbon

 

The results we obtained from the docking revealed that the known principle compounds from the natural products have very low binding pose energies when compared to the standard anti-viral drugs. Especially, bisdemethoxycurcumin a chief molecule from turmeric shows least binding energies among all the chosen compounds was found to be -10.5180 Kcal/mol of binding pose energy against SARS CoV-2 virus. Curcuminoids includes curcumin, demethoxycurcumin and demethoxycurcumin; small molecules from neem especially gedunin, gingerenone and piperine also have better binding pose energies with the novel viruses more than that of the standard drug.

 

Among the chosen anti-viral drugs, oseltamivir is the chief drug has the least binding pose energy was found to be -8.41777 Kcal/mol, which shows better activity against the novel coronavirus. By evaluating the docking results we hypothesized that bisdemethoxycurcumin and demethoxycurcumin of turmeric, gedunin of neem and gingerenone of ginger might have better inhibitory activity against SARS CoV-2. They showed better binding affinities with this virus having least binding pose energies as -10.5180, 10.4968, 10.0547 and -9.94035 Kcal/mol respectively. Further experimental approaches could be adopted to design the new drugs in-vitro and in-vivo using these principle components derived from turmeric, neem, ginger and pepper.

 

4. CONCLUSION:

At recent times, many countries are in demand for the drug against the SARS CoV-2, Nature has a remedy for all kind of problems especially against the contagious pathogens to human being. Scientists and Physicians are in search of potent drug for this communicable disease, but we look forward to these small molecules from turmeric, neem, ginger and pepper seems to be the gifts of god through nature, might be the potential drugs that inhibit the novel SARS CoV-2. In terms of minimizing the time factor this insilico research has been very essential tool to identify the probable drug and being an eye-opening. In mere future, it will lead into great interest in the field of medicine and better used for the synthesis of innovative drugs.

 

5. DECLARATION OF COMPETING INTEREST:

The authors declared that they have no conflict of interest.

 

6. ACKNOWLEDGMENTS:

The authors are thankful to the management of St. Xavier’s College (Autonomous), Palayamkottai and The Standard Fireworks Rajaratnam College for Women (Autonomous), Sivakasi, for their continued support.

 

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Received on 30.07.2020           Modified on 15.09.2020

Accepted on 26.10.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(9):4913-4919.

DOI: 10.52711/0974-360X.2021.00854