Mangostenone Bioactive Compound from Garcinia mangostana L. as Antiviral Agent via Dual Inhibitors Against E6 HPV 16/18 Oncoprotein through Computational Simulation

Viol Dhea Kharisma^1,2, Priscilla Listiyani², Ahmad Affan Ali Murtadlo²,

Rizal Adistya Putra Pradana², ANM Ansori³, Alexander Patera Nugraha⁴, Shilfiana Rahayu⁵, Cici Tya Rahmawati¹, Angelina Andreevna Obukhova⁶, Zurab Aslanovich Gasanov⁶,

Zalina Ahmedovna Dzaurova⁷, Ramazan Magomedgadjievich Osmanov⁶,

Marina Nikolaevna Sizonenko⁸, Maksim Rebezov^9,10, Vikash Jakhmola¹¹, Hery Purnobasuki¹, Dwi Kusuma Wahyuni¹*

¹Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia.

²Computational Virology Research Unit, Division of Molecular Biology and Genetics,

Generasi Biologi Indonesia Foundation, Gresik, Indonesia.

³European Virus Bioinformatics Center, Jena, Germany .

⁴Department of Orthodontics, Faculty of Dental Medicine,Universitas Airlangga, Surabaya, Indonesia.

⁵Department of Biology, Faculty of Science andTechnology,

Universitas Islam Negeri Sunan Kalijaga, Yogyakarta, Indonesia.

⁶Medical and Preventive Faculty, Rostov State Medical University, Rostov-on-Don, Russian Federation.

⁷Faculty of Pediatrics, Rostov State Medical University, Rostov-on-Don, Russian Federation.

⁸Medical and Biological Faculty, North Caucasus Federal University, Stavropol, Russian Federation.

⁹Department of Scientific Research, V. M. Gorbatov Federal Research Center for Food Systems,

Moscow Russian Federation.

¹⁰Faculty of Biotechnology and Food Engineering, Ural State Agrarian University,

Yekaterinburg, 620075, Russian Federation.

¹¹Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, India.

*Corresponding Author E-mail: dwi-k-w@fst.unair.ac.id

ABSTRACT:

HPV is a DNA virus from Papillomaviridae about 170 types have been identified and most of these viruses can triger cervial cancer disease. Types of HPV that can trigger cervical cancer consist of HPV-16 and HPV-18 with around 70% of cases, HPV-6 and HPV-11 only trigger genital warts. Types of HPV-16 and HPV-18 are high risk in triggering cervical cancer. High risk HPV types have the ability to interfere with the performance of tumor suppressors in cells through oncoprotein activity. E6 is a crucial oncoprotein because it allows degradation of tumor suppressors in host cells, E6 can be a major target in antiviral drug design. Inhibition of the E6 domain by antiviral candidate compounds is an important part of preventing the formation of the E6-p53 complex and preventing cancer development. Garcinia mangostana L. (Mangosteen) is a traditional medicine for treating bacterial, viral, fungal infections, as an antioxidant, and for degenerative diseases. This study aims to explore the potential of mangostenone compounds from Garcinia mangostana L. as HPV antivirals through inhibition of the E6 oncoprotein on HPV-16 and HPV-18 through in silico study. In silico analysis methods such as drug likeness, antiviral probability, docking simulation, chemical interaction analysis, and molecular visualization were used in this study to reveal HPV antiviral candidates from Mangostenone derivatives. Mangostenone derivative compounds from Garcinia mangostana L. can be antiviral candidates for HPV through a dual inhibitory mechanism by Mangostenone A. These compounds have strong activity through more negative binding affinity values and weak bonds such as hydrogen and hydrophobic bonds compared to other mangostenone derivative compounds.

KEYWORDS: Antiviral, Dual Inhibitors, Garcinia mangostana, HPV, Mangostenone.

INTRODUCTION:

The human papillomavirus (HPV) is a DNA virus from the Papillomaviridae family, about 170 types have been identified and most of these viruses can trigger warts or precancerous lesions. The risk of transmitting HPV infection increases through sexual contact such as multiple sexual partners, a weak immune system, and smoking habits^1,2. HPV can be transmitted from mother to baby during pregnancy, the toilet floor is also a medium for transmitting this virus, HPV is not killed by hand sanitizers and disinfectants. HPV infection can increase the risk of cancer of the vagina, cervix, vulva, penis, anus and mouth^3,4. Types of HPV that can trigger cervical cancer consist of HPV-16 and HPV-18 with around 70% of cases, HPV-6 and HPV-11 only trigger genital warts. Cases of cervical cancer due to HPV infection in the world have continued to increase since 2018 with 569,000 (new cases) identified and 311,000 (deaths), dominant transmission occurs through sexual contact.HPV has two types of proteins consisting of early (E) and late (L), protein E is produced by the virus at the start of the initiation stage of replication^4,5. Protein E plays a role in triggering oncoprotein expression, replication, and assembly of new viral particles, protein L is produced at the end of the replication stage for the formation of two layers of the capsid minor and major with a pentamer structure^6,7.

Types of HPV-16 and HPV-18 are high risk in triggering cervical cancer. High risk HPV types have the ability to interfere with the performance of tumor suppressors in cells through oncoprotein activity. Oncoproteins in HPV consist of E6 and E7 which play a role in triggering host cell immortalization. The E6 oncoprotein can form the E6-p53 complex to go through degradation via the proteasome, E7 works to inhibit pRb activation in the cell cycle then triggers check point disturbances^8,9,10. E6 can inhibit interferon and MHC representation which triggers the failure of natural antiviral responses through the detection of immune cells when an early stage of HPV infection occurs. E6 is a crucial oncoprotein because it allows degradation of tumor suppressors in host cells, E6 can be a major target in antiviral drug design. Inhibition of the E6 domain by antiviral candidate compounds is an important part of preventing the formation of the E6-p53 complex and preventing cancer development^11,12,13.

Herbal medicine and therapy were the best options according to traditional folklore^14,15. Some reports showed that many plants have been explored for combating some diseases¹⁶.

Garcinia mangostana L. (Mangosteen) is a plant belonging to the Clusiaceae family which is commonly found in Southeast Asia. The fruit of this plant is often used as a traditional medicine for treating bacterial, viral, fungal infections, as an antioxidant, and for degenerative diseases. Previous research reported that Garcinia mangostana L. can produce pharmacological effects in vitro as an anticancer. The chemical compounds from Garcinia mangostana L. consist of α-Mangostin, β-Mangostin, γ-Mangostin, Mangostenone A, Mangostenone B, Mangostenone C, Mangostenone D, and Mangostenone E¹⁴. Previous in silico studies have shown that identified mangostin compounds can inhibit the activity of Mpro SARS-CoV-2¹⁵. The potential of mangostenone derivative compounds as antivirals has not been identified. This study aims to explore the potential of mangostenone compounds from Garcinia mangostana L. as HPV antivirals through inhibition of the E6 oncoprotein on HPV-16 and HPV-18 through in silico study.

METHOD:

Ligand-protein Preparation:

Derivative compounds of Mangostenone from Garcinia mangostana L. in this study consisted of Mangostenone A, Mangostenone B, Mangostenone C, and Mangostenone D, and Mangostenone E¹⁴. CID compound, SMILE, cite and sdf files were obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/). 3D structures of E6 HPV-16 (PDB ID: 2FK4) and E6 HPV-18 (PDB ID: 2I04) in pdb format obtained from RCSB PDB (https://www.rcsb.org/). The conversion of sdf files to pdb was done via OpenBabel v2.3.1 for increased ligand flexibility and structural optimization¹⁶. Removal of water molecules and contaminant ligands on the target was performed via PyMol v2.5 for molecular docking preparation^17,18,19.

Druglikeness Identification and Antiviral Probability:

The nature of drug-like molecules in mangostenone derived compounds was identified through the Lipinski Rule of Five (http://www.scfbio-iitd.res.in/software/drugdesign/lipinski.jsp). The Lipinski Rule of Five is used to determine the query compound similarity to the drug molecule through various parameters such as molecular mass, hydrogen bond donor, hydrogen bond acceptor, LOGP, and molar refractivity. Query compounds must follow at least two rules to be categorized as drug-like molecules^20,21,22. Drug-like molecule compounds were then identified for antiviral probability through PASSOnline (http://www.pharmaexpert.ru/passonline/) for selection of candidate antiviral compounds based on probability^23,24. Prediction probability consists of activation (Pa) and inhibition (Pi), a positive result is shown at a score of Pa > 0.3 with medium confidence^25,26.

Screening Docking Simulation:

The inhibitory activity of Mangostenone derivatives on E6 HPV-16 and E6 HPV-18 in this study was identified through molecular docking on PyRx v0.9.9 software using the screening method. Screening docking aims to identify the activity of the ligand when it binds to a protein with an unidentified functional domain^27,28. The ability of the ligand activity is indicated by the binding affinity value. The autogrid was determined at position E6 HPV-16 Center (Å) X: 55.848 Y: 0.616 Z: 0.457 Dimensions (Å) X: 56.277 Y: 33.446 Z: 35.311, E6 HPV-18 Center (Å) X: 19.755Y: -1.580 Z: 15,541 Dimensions (Å) X: 66.923 Y: 32.224 Z: 42.203 with maximize set^29,30.

Chemical Interaction

Analysis of chemical bond interactions in this study was carried out through Protein Plus (https://proteins.plus/). The types of interactions shown through the server consist of hydrogen, hydrophobic, and pi^31,32. Weak bond interactions consisting of hydrogen, hydrophobic, pi/alkyl, van der Waals, and electrostatic contributes to triggering ligand activity in target proteins. The existence of weak bond interactions is predicted to produce optimal inhibitory activity in drug molecules^33,34.

3D Molecular Visualization:

The 3D structures of protein samples, ligands, and molecular complexes from the docking results in this study were displayed via PyMol v2.5. Visualization was performed by displaying the color of the ligand based on the type of atom and selecting a single stain on the protein. Types of cartoons, surfaces, and sticks were used in this study for structural selection of ligands and proteins^35,36,37.

RESULT AND DISCUSSION:

Garcinia mangostana L. (Mangosteen) is a plant belonging to the Clusiaceae family which is commonly found in Southeast Asia^38,39. The fruit of this plant is often used as a traditional medicine for treating bacterial, viral, fungal infections, as an antioxidant, and for degenerative diseases. Garcinia mangostana L¹⁴. consist of α-Mangostin, β-Mangostin, γ-Mangostin, Mangostenone A, Mangostenone B, Mangostenone C, Mangostenone D, and Mangostenone Eobtained from PubChem with CID, SMILE and cite numbers (Table 1).Visualization of 3D structures using sticks and color selection of mangostenone derivatives were performed using the PyMol v2.5 software.The 3D structures for HPV-16 (PDB ID: 2FK4) and E6 HPV-18 (PDB ID: 2I04) were visualized via PyMol v2.5 software. through cartoons, transparent surfaces, and color selection (Figure 1).

The inhibitory activity of Mangostenone derivative compounds on E6 HPV-16 and E6 HPV-18 in this study was identified through molecular docking⁴⁶. Docking simulation is used to identify the ability of a ligand to bind to a target protein⁴⁷. The level of activity is determined by the binding affinity value of the ligand-protein complex. Binding affinity is the negative bond energy that is formed from the interaction of ligands on specific protein domains.The docking results of the Mangostenone derivative compound from Garcinia mangostana L. with E6 HPV-16 and E6 HPV-18 showed that the Mangostenone A compound had a more negative binding affinity value consisting of -7.8 kcal/mol and -8.6 kcal/mol when bound to two targets (Table 3). Ligands with more negative binding affinity can trigger inhibitory activity. Mangosteone A is predicted to trigger inhibitory activity on the E6 HPV-16 and E6 HPV-18 proteins. Ligand-protein complexes in Mangostenone A and E6 from HPV-16 and 18 are displayed through 3D structures such as sticks on ligands and proteins with (rigid-transparent) surfaces, color selection was performed on proteins and ligands (Figure 2).

Table 2. Lipinski Rule of Five prediction results and antiviral probability.

Compound	CID	Ligand Minimize Energy (kcal/mol)	Binding Affinity (kcal/mol)
Compound	CID	Ligand Minimize Energy (kcal/mol)	E6 HPV-16	E6 HPV-18
Mangostenone A	509267	+406.29	-7.8	-8.6
Mangostenone B	21672078	+428.44	-7.7	-8.1
Mangostenone C	11546716	+596.71	-6.8	-6.6
Mangostenone D	11696901	+390.81	-7.5	-7.9
Mangostenone E	11495983	+502.30	-6.0	-7.3

Figure 2: Molecularvisualization of the ligand-protein complex. (A) Mangostenone A_E6 HPV-16 (B)Mangostenone A_E6 HPV-18

Identification of molecular interaction domains to determine the position and type of chemical bond interactions in the ligand-protein complex^48,49,50. Weak bond interactions are formed to trigger specific biological activity on the target. Weak bond interactions such as hydrogen, van der Waals, hydrophobic, and electrostatic interactions play an important role in the ability of ligands to trigger activity in the target protein^51,52,53. Mangostenone A interacts via Tyr15A and Tyr4A residues on the E6 HPV-16 domain with hydrogen and hydrophobic bonds, in the E6 HPV-18 domain there is interaction via Phe46B and Lys457B residues with hydrogen bonds and hydrophobic on Phe519B (Figure 3).Mangostenone A is predicted to trigger dual inhibitory activity on E6 HPV-16 and E6 HPV-18 through a binding site consisting of Tyr15, Tyr4, Phe46, and Lys457 with hydrogen and hydrophobic interactions.

Figure 3: Molecularinteraction of the ligand-protein complex. (A) Mangostenone A_E6 HPV-16 (B)Mangostenone A_E6 HPV-18

CONCLUSION:

Mangostenone derivative compounds from Garcinia mangostana L. can be antiviral candidates for HPV through a dual inhibitory mechanism by Mangostenone A. These compounds have strong activity through more negative binding affinity values and weak bonds such as hydrogen and hydrophobic bonds compared to other Mangostenone derivative compounds. We recommend the binding sites on E6 HPV-16 and HPV-18 from the results of this study as a reference for antiviral discovery targets. The antiviral potential of Mangosteone A from this study should be analyzed through in vivo and in vitro approaches to strengthen the evidence base.

ACKNOWLEDGMENT:

This work was supported by the Taman Husada Graha Famili Surabaya (Medicinal Plant Garden) and PT. Intiland Development Tbk.

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Received on 08.01.2023 Modified on 12.03.2023

Research J. Pharm. and Tech 2023; 16(11):5045-5050.

DOI: 10.52711/0974-360X.2023.00817

Compound	Lipinski Rule of Five					Antiviral Probability
Compound	Molecular Mass (Dalton)	Hydrogen Bond Donor	Hydrogen Bond Acceptors	LOGP	Molar Refractivity	Pa	Pi
Mangostenone A	460.000	2	6	6.311	130.337	0.393	0.039
Mangostenone B	462.000	2	6	6.231	129.624	0.422	0.026
Mangostenone C	442.000	4	8	3.517	115.080	0.413	0.030
Mangostenone D	396.000	3	6	4.752	107.547	0.472	0.014
Mangostenone E	444.000	5	8	3.331	117.080	0.710	0.003

Compound	CID	SMILE	Cite
Mangostenone A	509267	CC(=CCC1=C2C(=C3C=CC(OC3=C1O)(C)C)OC4=CC5=C(C=CC(O5)(C)C)C(=C4C2=O)O)C	https://pubchem.ncbi.nlm.nih.gov/compound/Mangostenone-A
Mangostenone B	21672078	CC(=CCC1=C2C(=C3CCC(OC3=C1O)(C)C)C(=O)C4=C(C5=C(C=C4O2)OC(C=C5)(C)C)O)C	https://pubchem.ncbi.nlm.nih.gov/compound/Mangostenone-B
Mangostenone C	11546716	CC(=CCC1=C(C(=CC2=C1C(=O)C3=C(C4=C(C=C3O2)OC(C4O)C(C)(C)O)O)O)OC)C	https://pubchem.ncbi.nlm.nih.gov/compound/Mangostenone-C
Mangostenone D	11696901	CC(=CCC1=C(C2=C(C=C1O)OC3=C(C2=O)C4=C(C(=C3)O)OC(CC4)(C)C)O)C	https://pubchem.ncbi.nlm.nih.gov/compound/Mangostenone-D
Mangostenone E	11495983	CC(=CCC1=C(C2=C(C=C1O)OC3=C(C2=O)C(=C(C(=C3)O)OC)CC(C(C)(C)O)O)O)C	https://pubchem.ncbi.nlm.nih.gov/compound/Mangostenone-E