Antiretroviral Effect Simulation from Black Tea (Camellia sinensis) via Dual Inhibitors Mechanism in HIV-1 and its Social Perspective in Indonesia

 

Viol Dhea Kharisma^1,2, Sasando Dhohan Kharisma³, Arif Nur Muhammad Ansori^2,4, Hanny Priskila Kurniawan⁵, Adiana Mutamsari Witaningrum⁶, Amaq Fadholly^2,4, Martia Rani Tacharina⁷*

¹Master Program in Biology, Faculty of Mathematic and Natural Sciences,

Universitas Brawijaya, Malang, Indonesia.

²Division of Molecular Biology and Genetics, Generasi Biologi Indonesia Foundation, Gresik, Indonesia.

³Departement of Sociology, Faculty of Social and Political Sciences,

Universitas Muhammadiyah Malang, Malang, Indonesia.

⁴Doctoral Program in Veterinary Science, Faculty of Veterinary Medicine,

Universitas Airlangga, Surabaya, Indonesia.

⁵Veterinary Clinician, Sunset Vet Clinic, Bali, Indonesia.

⁶Department of Veterinary Public Health, Faculty of Veterinary Medicine,

Universitas Airlangga, Surabaya, Indonesia.

⁷Department of Veterinary Microbiology, Faculty of Veterinary Medicine,

Universitas Airlangga, Surabaya, Indonesia.

 

ABSTRACT:

This study aims to investigate the general social perspective related to black tea (Camellia sinensis) as a traditional treatment in Indonesia, the potency of bioactive compounds in black tea as a dual inhibitor of the replication of HIV-1 as it inhibits the chemical interactions between ligands and target protein domain. The samples is prepared from specific databases that is about HIV-1 target protein, black tea chemical compounds, and HIV-1 drug compounds as positive control. After that the virtual screening, protein-ligand interaction, and molecular visualization tests were performed. Thirteen black tea compounds obtained from the database and 2 control compounds consisting of neverapine and darunavir. In addition, the 3D structure of the target protein from HIV-1 consisting of reverse transcriptase (RT) (ID 3LP1) and protease (PR) (ID 4HLA) was obtained from a protein database. Interestingly, the social perspective regarding HIV-1 treatment is predicted to be more likely to choose traditional medicine compared to the use of antiretroviral (ARV) drugs. Traditional medicine with black tea may be very popular among many people. In conclusion, almost all chemical compounds contained in black tea can inhibit the HIV-1 replication. Furthermore, there are two compounds that play an important role in the process because it is predicted to inhibit the biological activity of PR and RT in HIV-1, (-)-epicatechin-gallate and epigallocatechin-gallate called dual inhibitors.

 

 

 

INTRODUCTION:

Indonesian people were living with Human immunodeficiency virus type 1 (HIV-1) approximately 640,000 in 2018. Based on UNAIDS data, 46,000 people were newly infectedwith HIV-1 within the same year and there were 38,000 deaths from an AIDS-related illness. The number of AIDS-related deaths has increased by 60% since 2010, from 24,000 to 38,000 deaths. The new of HIV infections has decreased, however, from 63,000 to 46,000 in the same period¹. HIV-1 infections are major serious health in Indonesia. Highly active antiretroviral therapy (HAART), combination antiretroviral therapy (cART), and improvement antiviral therapy have been developed as therapeutic strategies to minimize attack and prevent spread of HIV infection. However, control of the disease has not yet been entirely implemented².

 

A retrovirus is a type of RNA virus that inserts a copy of its genome into the DNA of a host cell that it invades, thus changing the genome of that cell. HIV is a member of the genus Lentivirus, part of the family Retroviridae³. This virus has several coding genes such as group antigens (gag) and  polymerase gene (pol) which function as structural protein coding genes and viral replication⁴. Pol gene consists of reverse transcriptase (RT), protease (PR), and integrase (INT)⁵. However, this study only discuss RT and PR, RT HIV-1 has the role of converting RNA to DNA so that it can be recognized by the enzyme ligase in the host cell, while PR cuts the polypeptide from the translational resulting into smaller pieces undergoing the process of modification into a part of the virus HIV-1^6,7. This prompted some previous researchers to design HIV-1 drugs, because they already knew the important role of the target protein, RT and PR, on the mechanism of viral replication⁸.

 

Previously, a cure for HIV-1 infection called ARV was found, this drug is a type of non-nucleoside inhibitors (NNs) because it uses chemical compounds with simple structures⁹. NNs are called nevirapine on RT and darunavir on PR, both drugs are taken together by HIV-1 patients, which have a performance by binding to the target protein by producing weak binding interactions to produce biological activity in the form of inhibiting the activity of the target protein^10,11. The molecular interaction is the presence of hydrogen and hydrophobic bonding types which are often used as parameters in the in silico drug design study^12,13.

 

However, several studies in Indonesia revealed lack of recognition of the existence of the drug, because around 46% of the role of health workers in rural area did not conduct socialization even though there were still other factors such as awareness of PLWHA and environmental factors¹⁴. Therefore, there are people reluctant to take ARV because of the lack of recognition of these ARV drugs, but according to Jennifer and Saptutyningsih (2015) people in Indonesia prefer traditional medicine, for example black tea. This study used traditional medicine based on the chemical compounds are contained in black tea to generate theoretical predictions related to the use of black tea in HIV-1 infection cases¹⁵. Thus, this study aims to determine the general social perspective related to black tea as a traditional medicine in Indonesia, to investigate the potency of bioactive compounds in black tea as a dual inhibitor, and to predict the chemical interaction between ligands and target protein domains which might produce an inhibitory effect of HIV-1 replication.

 

MATERIAL AND METHODS:

Social Literature Study:

This study used the method of observation through several theories or data obtained from scientific articles in the social scope from national journals in Indonesia.

 

Samples:

Chemical compounds derived from black tea from previous studies¹⁶. Sample preparation of ligands or black tea compounds and controls was obtained on the PubChem database (pubchem.ncbi.nlm.nih.gov) by obtaining 3D structures in structure data format (.sdf). In addition, the preparation of the target protein is carried out by obtaining the 3D structure of the target protein in the format of the protein databank (.pdb) at PDB (rcsb.org). The target protein in this study consisted of PR and RT from HIV-1. The protein samples were first sterilized in PyMol software before the next analysis phase was carried out.

 

Virtual Screening:

In this study, the prediction of the activity of black tea compounds was performed using virtual screening methods via molecular docking with the VinaWizard plug-in on PyRx 0.8, but before the process was carried out, the first ligand went through a minimization process in OpenBabel plug-in so that it can get the format of the databank protein (pdb).

 

Protein-Ligand Interactions:

Complex molecules with scores of binding energy higher than control that were found in two protein targets and then analyzed for their interaction position and chemical bond formation type, using the webserver PoseView (proteins.plus). Output of this analysis were interaction position between atoms forming ligands and the type of chemical bonds formed during the interaction between ligands and protein.

 

Molecular Visualization:

In the final stage, molecular complexes were visualized in a representative form based on the selection of coloration and type of structure, molecular visualization in this study was carried out in PyMol.

 

RESULTS AND DISCUSSION:

Social Perspective of Black Tea in Indonesia:

Traditions are included in a particular belief or trait which is derived from a group of people with symbolic meaning from ancestors from ancient times, traditions can vary as forms of beliefs or habits such as animism, dynamism, and some activities in life¹⁷. One tradition that can be found in general is drinking tea, which has been carried on for a long time through parts of Asia, as is the case in Japan¹⁸. Although there are not many definite explanations of he existence of this tradition in Indonesia since ancient times, it is a common tradition and regularly practiced by Indonesians today. Tea can be classified as herbal medicine because it is one of the natural ingredients consisting of a number of chemical compounds, tea is usually taken for several purposes namely as a sedative agent and holistic (herbal) medicine^15,19.

 

The synthetic drugs used in computational simulations in this study are nevirapine and darunavir, both of which include ARV drugs that are often used to treat people with HIV-1 infection²⁰. However, a study concerning general awareness of these ARV drugs in Indonesia shows a devastatingly low number of people, especially HIV-1 sufferers, have any awareness of the existence of such drugs. This is speculated due to many factors, such as the lack of socialization by health workers in different regions (46%), the lack of awareness of ODHA (47,9%), and environmental factors as well (77%)¹⁴. Therefore, there are some people who are reluctant to take ARVs, and around 338,363 thousand people from 2005 to 2019 in Indonesia were infected with HIV-1 and in AIDS²⁰. However, according to Jennifer and Saptutyningsih (2015), most people in Indonesia believe more in herbal-based products such as herbal medicine to produce better efficacy than of synthetic drugs. This is also due to the increasing demand and use of natural-based medicines which are high as "back to nature" and “holistic” endorsements that raised because of the more available and cost-effective ingredients found in Indonesia^21,22,23, such as black tea.

 

The results of previous studies indicate that people in Indonesia often use black tea for antioxidant, antibacterial, and antifungal use, some also believe it can be used to treat obesity^24,25,26. However, research related to the potency of black tea for therapeutic treatment of viral infections such as HIV-1 in Indonesia is still unknown. Therefore, this study provides a deeper explanation, related to the potency of chemical compounds contained in black tea that can produce a therapeutic effect by inhibiting HIV-1 virus infection, so that many Indonesian people can find out the potency of black tea and researchers can conduct further research in this topic.

 

The Potency of Biochemical Compound from Black Tea as Antiretroviral Candidate via Dual Inhibitors Mechanism:

A total of 13 chemical compounds contained in black tea were obtained from the database, these compounds consisted of (-) epicatechin gallate (ID 107905), (-)-epigallocatechin gallate (ID 65064), chlorogenic acid (ID 1794427), (-)-epigallocatechin (ID 72277),               (-)epicatechin (ID 72276), caffein (ID 2519), pectin (ID 441476), theobromine (ID 5429), gallic acid (ID 370), and theanine (ID 228398). In addition, two control compounds were also obtained consisting of darunavir (ID 213039) (PR control) and nevirapine (RT control) (ID 213039). 3D structure of the target protein from HIV-1 consisting of RT (ID 3LP1) and PR (ID 4HLA) obtained from a protein database. Total sample of chemical compounds obtained from the database is 15 samples, which samples are in the .sdf format and must experience energy minimization in the OpenBabel plugin, so that the .pdb format is obtained and can be used in the next analysis (molecular docking). Samples of target proteins are displayed in PyMol software, with 3D visualization in the form of cartoon to find out the types of secondary protein constituents, transparent and rigid surfaces, and color selection based on the purpose of visualizing the structure comparison and differences in the chain making up a protein. In addition, sterilization of the two target proteins was performed to eliminate contaminant molecules, which consisted of undesired water, ligands, and peptides. After the sterilization process was successful, the target protein was stored in the form of a .pdb file without contaminants when re-visualizing. The results of the visualization of the target protein structure (Figure 1) showed that everything was composed of secondary protein structures in the form of cartoons, namely alpha helix (red), coil (green), and beta-sheet (yellow). But for RT only has one chain, namely chain A which is marked by visualization of the rigid surfaces structure in green, while PR consists of two chains, A and B.

 

 

Figure 1. Molecular visualization of comparison of target protein structures. (A) Reverse transcriptase; and (B) Protease. Structure displayed (left) with white transparent surfaces with cartoon structure colored based on the secondary protein structure and composition of rigid surface (right) with domain selection based on chains.

 

After the preparation of the ligand and target, the molecular docking process was carried out, this analysis aimed to determine the effect of ligand binding with the target protein that leads to a biological response. Docking is a simulation of the interaction between molecules with one another to determine the interaction pattern model and the amount of binding energy, with the help of bioinformatics software¹⁶. The amount of binding energy resulting from docking refers to Gibbs' law, if a ligand has a negative binding energy value, the effect is greater on the target protein²⁷. One docking method is blind, its aimed at screening the potential compounds with a functional side of an unknown protein²⁸. This research uses blind docking method because it aims to screen the potency of black tea chemical compounds that produce a biological response in the form of inhibition of activation of target proteins. The grid position in this study is in all parts of the target protein, thus allowing ligand binding to all parts (Table 1). The grid is a cube that directs the ligand binding to the position of target protein domain, when docking analysis has performed.

 

Based on the results of the study showed the docking on RT (Table 2) has about 13 chemical compounds from black tea with lower binding energy compared to controls consisting of -8.5 kcal/mol (-)epicatechin (ID 72276), -8.4 kcal/mol (-)-epigallocatechin (ID 72277), -8.2 kcal/mol (-)epicatechin gallate (ID 107905), -7.8 kcal/mol (-)-epigallocatechin gallate (ID 65064), -7.1 kcal/mol chlorogenic acid (ID 1794427), -6.4 kcal/mol gallic acid (ID 370), -6.2 kcal/mol theobromine (ID 5429), and -6.1 kcal/mol nevirapine (Control) (ID 213039). However, in PR (Table 3) only 2 compounds consisted of -9.4 kcal/mol (-)Epicatechin gallate (ID 107905), -9.3 kcal/mol (-)-epigallocatechin gallate (ID 65064), and -8.7 darunavir (Control) (ID 213039). Interestingly, there are two compounds having lower binding energy under control drug that can bind to both target proteins, namely (-)epicatechin gallate (ID 107905) and (-)-epigallocatechin gallate (ID 65064).

 

Control compounds under normal conditions work to inhibit the biological activity of the target protein, by binding and forming molecular complexes. Nevirapine is a drug used as an inhibitor of RT HIV-1. The mechanism of binding to the active side of the target protein uses the interaction of hydrophobic bonds, thus blocking RT activation²⁹. Darunavir plays a role in inhibiting the performance of PR HIV-1 through the interaction of hydrogen bonds on the active side of PR called the catalytic site³⁰. The docking results show that some binding energy scores produced by the ligand against the two target proteins thus influencing the biological activity of the protein. Ligands, which have a greater binding energy than controls, have a greater affect on the target protein¹⁶.

 

Table 1. Docking Grid Position.

   *Note: RT: Reverse Transcriptase; PR: Protease.

 

 

Table 2. The Docking Results of Black Tea Compounds with RT HIV-1.

Ligand	PubChem ID	Target Protein	Binding Energy (kcal/mol)
(-) Epicatechin (-)-Epigallocatechin (-) Epicatechin gallate (-)-Epigallocatechin gallate Chlorogenic Acid Gallic Acid Theobromine Nevirapine (Control) Theanine Pectin Caffein	72276   72277 107905   65064     1794427 370 5429 213039   228398 441476 2519	HIV-1 RT   HIV-1 RT HIV-1 RT   HIV-1 RT     HIV-1 RT HIV-1 RT HIV-1 RT HIV-1 RT   HIV-1 RT HIV-1 RT HIV-1 RT	-8.5   -8.4 -8.2   -7.8     -7.1 -6.4 -6.2 -6.1   -5.9 -5.8 -5.2

 

 

Table 3. The Docking Results of Black Tea Compounds with PR HIV-1.

Ligand	Pub. Chem ID	Target Protein	Binding Energy (kcal/mol)
(-) Epicatechin gallate (-)-Epigallocatechin gallate Darunavir (Control) Chlorogenic Acid (-)-Epigallocatechin (-) Epicatechin Caffein Pectin Theobromine Gallic Acid Theanine	107905   65064     213039   1794427 72277   72276 2519 441476 5429 370 228398	HIV-1 PR HIV-1 PR   HIV-1 PR   HIV-1 PR HIV-1 PR   HIV-1 PR HIV-1 PR HIV-1 PR HIV-1 PR HIV-1 PR HIV-1 PR	-9.4   -9.3     -8.7   -8.2 -8.1   -8.1 -5.8 -5.6 -5.6 -5.5 -5.3

 

Thus, black tea chemical compounds can potentially inhibit the activity of the target protein, which must have a more negative binding energy value than the control. However, there are two compounds that can potentially inhibit and therefore work as dual inhibitors to the two target proteins, namely (-) epicatechin gallate and (-)-epigallocatechin gallate. The compounds from docking analysis, that act as dual inhibitors are displayed on PyMol software with cartoon structures and transparent surfaces.

 

The Molecular Interaction between Ligand and Protein:

When a ligand is bound to a protein it forms complex molecules, which produces molecular interactions in the form of chemical bonds. The chemical bonds in the form of weak bond interactions consist of hydrophobics and hydrogen in the ligand-making atoms with amino acid residues in the target protein^12,13. Potential ligands as dual inhibitors are then identified by the type of chemical bond interaction and the position of amino acid residues in the target protein using the Pose View webserver. The black tea compound (-) epicatechin gallate binds to PR with a total of seven molecular interactions consisting of six hydrogen bonds (Asp29A, Gly48A, 2 Arg8B, Gly27A, and Gly27B) and one hydrophobic (Ile50B), while the compound (-)-epigallocatechin gallate binds to PR and has a total number of molecular interactions of seven, all in the form of seven hydrogen bonds (2 Arg8B, Gly27A, Gly27B, Asp29A, and 2 Gly48A). The darunavir has nine molecular interactions, four hydrogen bonds (Arg8A, Asp25A, Gly48A, and Asp29B) and five hydrophobic (Asp30B, Ile50A, Ile84B, Ile47B, and Gly49A) (Figure 2). The compound (-) epicatechin gallate bounded to RT has a molecular interaction of seven in the form of four hydrogen bonds (Asn103A, Lys101A, Ile180A, and Gly99A) and three hydrophobic (Val179, Leu100A, and Tyr181A). While the compound (-)-epigallocatechin gallate bounded to RT has a molecular interaction of six with four hydrogen bonds (Ile180A, Gly99A, Lys101A, and Asn103A) and two hydrophobics (Leu100A and Val179). The nevirapine control has two molecular interactions, one hydrogen bond (Thr107A) and one hydrophobic (Pro225) (Figure 3).

 

Molecular interactions identified based on the results of this study are hydrogen and hydrophobic bonds. Hydrogen bonding is a chemical bond produced by the interaction of H atoms with N, O, F and as a parameter of ligand tendency can play a role in influencing the biological response of target proteins in drug design strategies, in addition to hydrophobic bonds^31,32. Hydrophobic bonds take form of molecular complexes and play a role in the interaction of drug molecules, thereby inducing a significant change in biological response to the protein target³³. The existence of the hydrogen interaction and hydrophobic that are formed in molecular complexes, from the results of this study indicates that ligands consisting of black tea compounds and controls interact with the target protein and affect the biological response of the protein. Returning back to the purpose of this study which is to reveal compounds that are dual inhibitors of HIV-1, we obtain of two compounds in the form of -(-)epicatechin gallate and                -(-)epigallocatechin gallate have strong interactions with two target virus proteins with a binding energy value greater than control and inhibiton of the types of chemical bonds of molecular interactions that support their affect.

 

Thus, black tea is predicted to be able to inhibit HIV-1 infection through the binding mechanism of chemical compounds bind to RT and PR, which protein has an important role in the process of viral replication. All chemical compounds that have lower binding energy value compared to control, and affect the biological response for target. In this study, we revealed the two compounds, -(-)epicatechin gallate and                                      -(-)epigallocatechin gallate, have the lowest binding energy and act as inhibit the responses of biological activity of the target protein.

 

Figure 2. Molecular visualization of docking results of black tea compounds with PR. A: (-)-epicatechin-gallate-PR; B: (-)-epigallocatechin-gallate-PR; and C: darunavir-PR.

 

Figure 3. Molecular visualization of docking results of black tea compounds with RT. A: (-)-epicatechin-gallate-RT; B: (-)-epigallocatechin-gallate-RT; and C: nevirapine-RT.

 

CONCLUSION:

In sum, the social preference regarding HIV-1 treatment is herbal traditional medicine compared to ARV drugs, traditional medicine with black tea in the future might be sought after by the community. In addition, almost all of the chemical compounds contained in black tea can inhibit the replication of the HIV-1 virus, but there are two compounds that play an important role for their dual inhibition benefits. They can inhibit both the biological activity of PR and RT in HIV-1, (-)-epicatechin gallate and (-)epigallocatechin gallate.

 

ACKNOWLEDGEMENT:                       

This study was supported by the Ministry of Research, Technology, and Higher Education of the Republic of Indonesia.   

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 23.02.2020           Modified on 01.04.2020

Accepted on 09.05.2020         © RJPT All right reserved