Revealing Novel Antiretroviral Candidate from Garcinia mangostana L. againts HIV-1 Infection via Reverse Transcriptase Inhibition:

In Silico Study

Viol Dhea Kharisma^1,2, Arif Nur Muhammad Ansori^1,3, Ahmad Affan Ali Murtadlo²,

Maksim Rebezov^4,5, Nikolai Maksimiuk⁶, Pavel Burkov⁷, Marina Derkho⁷, Elena Bobkova⁸,

Evgeny Ponomarev⁸, Vikash Jakhmola⁹, Hery Purnobasuki^1,10*

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.

³Professor Nidom Foundation, Surabaya, Indonesia.

⁴Department of Scientific Research, V. M. Gorbatov Federal Research Center for Food Systems,

Moscow, Russian Federation.

⁵Faculty of Biotechnology and Food Engineering, Ural State Agrarian University,

Yekaterinburg, Russian Federation.

⁶Institute of Medical Education, Yaroslav-the-Wise Novgorod State University,

Velikiy Novgorod, Russian Federation.

⁷Institute of Veterinary Medicine, South Ural State Agrarian University, Troitsk, Russian Federation.

⁸K.G. Razumovsky Moscow State University of Technologies and Management (The First Cossack University), Moscow, Russian Federation.

⁹Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.

¹⁰Biotechnology of Tropical Medicinal Plants Research Group, Universitas Airlangga.

*Corresponding Author E-mail: hery-p@fst.unair.ac.id

ABSTRACT:

Human immunodeficiency virus (HIV) is a genus of Lentivirus that triggers opportunistic diseases in the human body. HIV-1 has been a major problem for the world community for a long time and triggered a pandemic. HIV-1 antiviral drugs with the mechanism of inhibiting specific proteins have been found but have some harmful side effects for patients. Back to nature solutions can be used to solve these problems. Natural ingredients can be used as an alternative treatment for the treatment of HIV-1 infection allegedly more effective and minimal side effects. Antiviral candidate natural ingredients such as Garcinia mangostana L. with compounds consisting of Mangostin and Garcinone, the potential of Garcinone compounds is currently still unidentified. This study aims to reveal the potential of Garcinone derivative compounds from Garcinia mangostana L. as HIV-1 antiviral through the mechanism of reverse transcriptase inhibition with an in silico approach. The method used in this research is in silico simulation such as druglikeness analysis, molecular docking, chemical bond identification, and molecular stability. Garcinone A from Garcinia mangostana L. can be an HIV-1 antiviral candidate with a good molecular mechanism of inhibiting HIV-1 RT activity because it produces more negative binding affinity than the control drug and triggers stable binding interactions on the target.

KEYWORDS: Antiviral, Garcinia mangostana, Garcinone, HIV-1.

INTRODUCTION: 

Human immunodeficiency virus (HIV) is classified in the genus Lentivirus in the family Retroviridae or subfamily Orthoretrovirinae. The currently identified types of HIV are HIV-1 and HIV-2. Cases of HIV-2 infection are endemic in specific countries such as Africa, but HIV-1 infection has been a pandemic since around 1940. The origin of HIV was identified from viruses infecting Central African chimpanzees (SIVcpz) for HIV-1 and HIV-2 from West African sooty mangabeys (SIVsm)^1,2. HIV-1 is the focus of this study because the pandemic triggered by the virus is still happening, HIV-1 has a higher prevalence than HIV-2 and more mutated variants. HIV is a single-stranded RNA (ssRNA) virus with a very high probability of genetic replication errors compared to DNA viruses^3,4. The increase in HIV-1 variants is the main cause of the severity of the pathogenesis of viral infections in host cells. HIV infection triggers complications in a person's body called Acquired Immune Deficiency Syndrome (AIDS), AIDS is indicated by a decrease in the number of CD4⁺ lymphocytes and increased infection by other pathogens due to a decrease in the body's immune response^5,6. HIV-1 drug design research conducted by previous studies focused on inhibiting viral replication enzymes.

HIV-1 drugs are referred to as antiretrovirals (ART), which consist of two types: nucleoside and non-nucleoside. An example of ART is Azvudine which acts to inhibit the reverse transcriptase enzyme used to treat HIV-1 infection^7,8. The use of Azvudine has been approved by China since 2021 in combination with other inhibitors, but this drug also has side effects such as tiredness, fever, insomnia, elevated liver enzymes, and several other side effects⁹. Reverse transcriptase (RT) in HIV plays a role in the formation of HIV cDNA during the replication process before the virus assembly process takes place¹⁰. RT inhibitors generally work by forming hydrogen and hydrophobic interactions to inhibit the formation of open structures in RT^11,12. The open structure in RT allows the reverse transcription of ssRNA into HIV-1 cDNA, RT inhibitors can inhibit this process to work as an antiviral.

Current RT inhibitors are based on synthetic compounds with various side effects that may be harmful if consumed long-term^13,14. The use of natural ingredients as an alternative treatment for the treatment of HIV-1 infection is thought to be more effective and minimal side effects¹⁵. Antiviral candidate natural ingredients such as Garcinia mangostana L. with compound content consisting of Mangostin and Garcinone, the potential of Garcinone compounds is currently still unidentified, Garcinone compounds have derivates consisting of Garcinone A, Garcinone B, Garcinone C, Garcinone D, and Garcinone E^16,17. However, Garcinia mangostana L. extract has been shown to inhibit the replication of a type of virus and is proven through in vitro and in vivo studies with unknown mechanisms. The in silico approach can be used to predict the molecular mechanism of activity of a natural material to produce antiviral potential^18,19,20. This study aims to reveal the potential of Garcinone derivative compounds as HIV-1 antiviral through the mechanism of reverse transcriptase inhibition with an in silico approach.

METHOD:

Ligand Retrieval:

Chemical compounds of Garcinone derivative from Garcinia mangostana L. such as Garcinone A, Garcinone B, Garcinone C, Garcinone D, and Garcinone E act as ligands obtained from PubChem database (https://pubchem.ncbi.nlm.nih.gov/).Retrieval of ligand information in the database consists of compound name, formula, CID, SMILE, and .sdf file. This study also used a control drug, Azvudine (CID 24769759) to compare inhibitor activity on HIV-1 RT with Garcinone^21,22,23.

Protein Preparation:

Inhibitor target in this study was reverse transcriptase of HIV-1 obtained from Protein Databank (RCSB PDB) database (https://www.rcsb.org/)with PDB ID: 1REV^24,25. RT is one of the functional proteins of HIV-1 plays a role in the mechanism of virus assembly at the replication stage, RT inhibitors work to disrupt and trigger the failure of the HIV-1 replication process^26,27,28.

Lipinski Rule of Five’s Assessment:

Druglikeness analysis aims to identify the similarity of activity of Garcinone derivative compounds from Garcinia mangostana L. with drug molecules referring to Lipinski Rule of Five's (http://www.scfbio-iitd.res.in/software/drugdesign/lipinski.jsp).This rule identifies drug-like molecules in query compounds based on molecular mass, refractivity, hydrogen bond donors-acceptors, and high lipophilicity (LogP)^29,30,31.

Antiviral Prediction:

Identification of antiviral probabilities on Garcinone derivative compounds from Garcinia mangostana L.were performed through the PASS Online server (http://way2drug.com/PassOnline/)^32,33. Predictions based on probability activation (Pa) and probability inhibition (Pi), the value of Pa used in this study is medium confidence, namely Pa> 0.3 for positive predictions^34,35,36.

Virtual Screening:

Virtual screening conducted in this study is molecular docking for identification of ligand activity on the target. The process of minimization and conversion of .sdf to .pdb files on the ligand were performed through OpenBabel v2.3.1 software and the removal of water molecules and native ligands on the target were performed through PyMOL v.2.5.2 software (Schrödinger, Inc., USA) with an academic license^37,38. The grid in the docking simulation aims to direct the binding of the query ligand to specific domains on the target. The docking grid on HIV-1 RT domain is Center (Å) X: 20.322 Y: -30.071 Z: 23.184 Dimensions (Å) X: 52.087 Y: 56.028 Z: 49.800, simulations were performed through software through PyRx v1.0 (Scripps Research, USA) with an academic license, and visualization of docking results on PyMOL v.2.5.2 software (Schrödinger, Inc., USA)^39,40,41.

Ligan-protein Interaction:

The molecular interactions in the ligand-protein complexes from the docking simulation analysis results were identified through Discovery Studio Visualizer™ v.16.1 software (Dassault SystèmesSE, France)^42,43. The software can identify the types of molecular interactions such as hydrogen, hydrophobic, pi/alkyl, electrostatic, and van der Waals bonds formed in the ligand-protein complex^44,45.

Molecular Dynamic Simulation:

Stability simulation of bond interactions in the target domain is identified through molecular dynamic analysis through the CABS-flex 2.0 server (http://biocomp.chem.uw.edu.pl/CABSflex2/index)with referring to the root-mean-square fluctuation (RMSF) value. Some of the parameters used in the server are rigidity, C-alpha, side chain restraints, number of cycles, cycles between trajectories, temperature range, and RNG seed^46,47.

RESULTS AND DISCUSSION:

Garcinia mangostana L. is used by people in the world as an alternative medicine such as an anti-inflammatory, antioxidant, and antidiabetic⁴⁸. Previous research reported the potential of chemical compounds from Garcinia mangostana L^49,50. as antiviral identified through in vitro studies with unknown molecular mechanisms. Garcinia mangostana L. has Garcinone derivate compounds consisting of Garcinone A, Garcinone B, Garcinone C, Garcinone D, and Garcinone E. 3D samples of all Garcinone derivate compounds and other information such as CID, formula, molecular weight (g/mol), and SMILE in this study were obtained from the PubChem database (Table 1). 3D visualization of Garcinone derivative compounds (Figure 1) and HIV-1 RT structure obtained from RCSB PDB database with ID: 1REV (Figure 2) was performed through PyMOL v.2.5.2 software (Schrödinger, Inc., USA).

Table 1: Ligand sample informations from database

Compound	CID	Formula	Molecular Weight (g/mol)	SMILE
Garcinone A	70689919	C23H24O5	380.4	CC(=CCC1=C(C(=C2C(=C1O)C(=O)C3=C(O2)C=C(C=C3)O)CC=C(C)C)O)C
Garcinone B	5495928	C23H22O6	394.4	CC(=CCC1=C(C2=C(C=C1O)OC3=C(C2=O)C4=C(C(=C3)O)OC(C=C4)(C)C)O)C
Garcinone C	44159808	C23H26O7	414.4	CC(=CCC1=C(C2=C(C=C1O)OC3=C(C2=O)C(=C(C(=C3)O)O)CCC(C)(C)O)O)C
Garcinone D	5495926	C24H28O7	428.5	CC(=CCC1=C(C2=C(C=C1O)OC3=C(C2=O)C(=C(C(=C3)O)OC)CCC(C)(C)O)O)C
Garcinone E	10298511	C28H32O6	464.5	CC(=CCC1=C(C2=C(C=C1O)OC3=C(C(=C(C(=C3C2=O)CC=C(C)C)O)O)CC=C(C)C)O)C

Figure 1: Molecular visualization of Garcinone derivative compound from Garcinia mangostana L. as ligand. The 3D structure of the ligand is shown with sticks and colors based on C (green), H(gray), O(red), and N(blue) atoms. (A) Garcinone A (B) Garcinone B (C) Garcinone C (D) Garcinone D (E) Garcinone E (F) Azvudine or HIV-1 control drug.

Figure 2: 3D representation of HIV-1 RT targets with three types of structures. (A) Cartoons with secondary protein-based colors (by SS) (B) Rigid surfaces (C) Cartoons with transparent surfaces

Table 2. The result of druglikeness analysis

Compound	Molecular Mass (≥500 Dalton)	HBD (≤5)	HBA (≤10)	LOGP (≤5)	Molar Refractivity (40-130)	Probable
Garcinone A	380.000	3	5	5.157	107.654	Drug-like molecule
Garcinone B	394.000	3	6	4.833	108.260	Drug-like molecule
Garcinone C	414.000	5	7	4.057	110.803	Drug-like molecule
Garcinone D	428.000	4	7	4.360	115.690	Drug-like molecule
Garcinone E	464.000	4	6	6.371	132.454	Drug-like molecule

Druglikeness analysis aims to identify the similarity of physicochemical properties of query compounds with the activity of drug molecules by specific rules^51,52. Lipinski Rule of Five's (Ro5) was used in this study for assessment of the query ligand as a drug-like molecule⁵³. The physicochemical parameters in Ro5 for assessment consist of molecular mass (≥500 Dalton), hydrogen bond donor (≤5), hydrogen bond acceptor (≤10), high lipophilicity (≤5), and molar refractivity (40-130)⁵⁴. The query compound must fulfill at least two rules from Ro5 to be a positive prediction as a drug-like molecule. Garcinone derivatives from Garcinia mangostana L. are drug-like molecules because all fulfill at least two rules of Ro5 (Table 2).

Garcinone derivative compound from Garcinia mangostana L. as drug-like molecule on RT HIV-1 should be further tested through molecular docking simulation. This simulation aims to identify the activity of ligand interaction on the target domain based on the level of binding affinity value^55,56. Binding affinity is the negative bond energy formed when the ligand interacts with the target, the more negative the binding affinity, the stronger the ligand activity such as inhibitory ability^57,58. The docking simulation results show Garcinone A has a more negative binding affinity of -9.0 kcal/mol than other Garcinone derivate compounds and the control drug Azvudine (Table 3), indicating Garcinone A can have better inhibitory activity on HIV-1 RT. 3D visualization of ligand-protein complexes was performed with sticks, transparent surfaces, and cartoons (Figure 3). The more negative binding affinity value of the query compared to the comparator drug indicates better inhibitory ability, the query compound has the potential to be a new antiviral agent⁵⁹.

Table 3: Binding affinity from the docking simulation

Compound	CID	Target	PDB ID	Docking Mode	Binding Affinity (kcal/mol)
Garcinone A	70689919	RT HIV-1	1REV	0	-9.0
Garcinone B	5495928	RT HIV-1	1REV	0	-8.5
Garcinone C	44159808	RT HIV-1	1REV	0	-8.5
Garcinone D	5495926	RT HIV-1	1REV	0	-8.3
Garcinone E	10298511	RT HIV-1	1REV	0	-8.3
Azvudine (Control)	24769759	RT HIV-1	1REV	0	-7.8

Figure 3. Ligand-protein complex. (A) Garcinone A-RT (B) Garcinone B-RT (C) Garcinone C-RT (D) Garcinone D-RT (E) Garcinone E-RT (F) Azvudine-RT.

Chemical bonding interactions in ligand-protein complexes are weak bonds such as hydrogen, van der Waals, electrostatic, alkyl, pi, and hydrophobic. Weak bonds act to increase the stability of a molecular complex and produce inhibitory activity⁶⁰. Antiviral candidates from previous studies also work through inhibitory mechanisms on targets by generating several weak bonds⁶¹. The identification of weak bonds and interaction positions on Garcinone A-RT shows that the ligand interacts with amino acid hot spots consisting of Leu26, Asn136, Thr139, Ser134, Asn137, Gly141, Ile132, Pro140, Thr131, Trp88, and Gln91 through van der Waals bonds, Gln23 through hydrogen bonds, and Val381, Pro25, Trp24, Pro133, and Lys22 with pi-Alkyl bonds (Figure 4A). The query compounds with more negative binding affinity were further analyzed through molecular dynamics to identify the stability of the ligand-protein complex. Molecular complex stability refers to RMSF values >3 or 4 (Å) at interaction hot spots. RMSF represents the conformational fluctuations in the target binding domain when a ligand-protein molecular complex is formed⁶². Garcinone A-RT produces a stable RMSF >3 (Å) at interaction hot spots (Figure 4B), which allows the formation of stable molecular complexes and triggers inhibitory activity on the target.

Figure 4. Molecular visualization of chemical interaction and dynamic fluctuation plot. (A) Garcinone A-RT 2D interaction (B) Garcinone A-RT RMSF plot.

CONCLUSION:

Garcinone A from Garcinia mangostana L. can be an HIV-1 antiviral candidate with a good molecular mechanism of inhibiting HIV-1 RT activity because it produces more negative binding affinity than the control drug and stable binding interactions on the target. Garcinone can form weak bonds for the stability of molecular complexes such as hydrogen, van der Waals, and pi-alkyl, but the results of this study should be further tested through in vitro and in vivo approaches to strengthen scientific evidence.

ACKNOWLEDGMENT:

This study supported by Hibah Riset Mandat from Universitas Airlangga, Surabaya, Indonesia.

REFERENCES:

1. Sharp PM, Hahn BH. Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med. 2011;1(1): a006841. DOI: 10.1101/cshperspect.a006841.

2. Adhiambo M, Makwaga O, Adungo F, Kimani H, Mulama DH, Korir JC, Mwau M. Human immunodeficiency virus (HIV) type 1 genetic diversity in HIV positive individuals on antiretroviral therapy in a cross-sectional study conducted in Teso, Western Kenya. Pan Afr Med J. 2021; 38: 335. DOI: 10.11604/pamj.2021.38.335.26357.

3. Rawat P, Teodorof-Diedrich C, Spector SA. Human immunodeficiency virus Type-1 single-stranded RNA activates the NLRP3 inflammasome and impairs autophagic clearance of damaged mitochondria in human microglia. Glia. 2019; 67(5): 802-824. DOI: 10.1002/glia.23568.

4. Giraldo DM, Hernandez JC, Urcuqui-Inchima S. HIV-1-derived single-stranded RNA acts as activator of human neutrophils. Immunol Res. 2016; 64(5-6): 1185-1194. DOI: 10.1007/s12026-016-8876-9.

5. Vidya Vijayan KK, Karthigeyan KP, Tripathi SP, Hanna LE. Pathophysiology of CD4+ T-Cell Depletion in HIV-1 and HIV-2 Infections. Front Immunol. 2017; 8: 580. DOI: 10.3389/fimmu.2017.00580.

6. Ratnam M, Nayyar AS, Reddy DS, Ruparani B, Chalapathi KV, Azmi SM. CD4 cell counts and oral manifestations in HIV infected and AIDS patients. J Oral Maxillofac Pathol. 2018; 22(2): 282. DOI: 10.4103/jomfp.JOMFP_191_17.

7. Wang RR, Yang QH, Luo RH, Peng YM, Dai SX, Zhang XJ, Chen H, Cui XQ, Liu YJ, Huang JF, Chang JB, Zheng YT. Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro. PLoS One. 2014; 9(8): e105617. DOI: 10.1371/journal.pone.0105617.

8. Li G, Wang Y, De Clercq E. Approved HIV reverse transcriptase inhibitors in the past decade. Acta Pharm Sin B. 2022;12(4): 1567-1590. DOI: 10.1016/j.apsb.2021.11.009.

9. Yu B, Chang J. Azvudine (FNC): a promising clinical candidate for COVID-19 treatment. Signal Transduct Target Ther. 2020; 5(1): 236. DOI: 10.1038/s41392-020-00351-z.

10. Singh AK, Das K. Insights into HIV-1 Reverse Transcriptase (RT) Inhibition and Drug Resistance from Thirty Years of Structural Studies. Viruses. 2022;14(5):1027. DOI: 10.3390/v14051027.

11. Xavier Ruiz F, Arnold E. Evolving understanding of HIV-1 reverse transcriptase structure, function, inhibition, and resistance. Curr Opin Struct Biol. 2020; 61: 113-123. DOI: 10.1016/j.sbi.2019.11.011.

12. Larsen KP, Mathiharan YK, Kappel K, Coey AT, Chen DH, Barrero D, Madigan L, Puglisi JD, Skiniotis G, Puglisi EV. Architecture of an HIV-1 reverse transcriptase initiation complex. Nature. 2018; 557(7703): 118-122. DOI: 10.1038/s41586-018-0055-9.

13. Kim MJ, Kim SW, Chang HH, Kim Y, Jin S, Jung H, Park JH, Kim S, Lee JM. Comparison of Antiretroviral Regimens: Adverse Effects and Tolerability Failure that Cause Regimen Switching. Infect Chemother. 2015; 47(4): 231-8. doi: 10.3947/ic.2015.47.4.231.

14. Hughes Y, Tomlins L, Usherwood T. Prescribing for patients taking antiretroviral therapy. Aust Prescr. 2022; 45(3): 80-87. DOI: 10.18773/austprescr.2022.026.

15. Kelso-Chichetto NE, Okafor CN, Harman JS, Canidate SS, Cook CL, Cook RL. Complementary and Alternative Medicine Use for HIV Management in the State of Florida: Medical Monitoring Project. J Altern Complement Med. 2016; 22(11): 880-886. DOI: 10.1089/acm.2016.0190.

16. Ansori ANM, Fadholly A, Hayaza S, Susilo RJK, Inayatillah B, Winarni D, Husen SA. A Review on Medicinal Properties of Mangosteen (Garcinia mangostana L.). Res J Pharm Techol. 2020; 13(2): 974-982. DOI: 10.5958/0974-360X.2020.00182.1

17. Espirito Santo BLSD, Santana LF, Kato Junior WH, de Araújo FO, Bogo D, Freitas KC, Guimarães RCA, Hiane PA, Pott A, Filiú WFO, Arakaki Asato M, Figueiredo PO, Bastos PRHO. Medicinal Potential of Garcinia Species and Their Compounds. Molecules. 2020; 25(19): 4513. DOI: 10.3390/molecules25194513.

18. Ben Hlima H, Farhat A, Akermi S, Khemakhem B, Ben Halima Y, Michaud P, Fendri I, Abdelkafi S. In silico evidence of antiviral activity against SARS-CoV-2 main protease of oligosaccharides from Porphyridium sp. Sci Total Environ. 2022; 836: 155580. DOI: 10.1016/j.scitotenv.2022.155580.

19. Tungary E, Ongko J, Sukweenadhi J, Antonius Y. Molecular docking of active compounds from traditional medicinal plants as ACE-2 protein (1R4L) inhibitor in searching for COVID-19 drug. Res J Pharm Technol. 2022; 15(9): 4235-4240. DOI: 10.52711/0974-360X.2022.00712

20. Antonius Y, Ongko J, Hardjo PH. Identification of potential activity of volatile compounds derived from Pogostemon cablin Benth as antiviral of SARS-CoV-2. Int J App Pharm. 2023; 15(1): 93-97. DOI: 10.22159/ijap.2023v15i1.43571

21. Fadholly A, Ansori ANM, Utomo B. Anticancer Effect of Naringin on Human Colon Cancer (WiDr Cells): In Vitro Study. Research Journal of Pharmacy and Technology. 2022; 15(2): 885-888. DOI: 10.52711/0974-360X.2022.00148

22. Husen SA, Wahyuningsih SPA, Ansori ANM, Hayaza S, Susilo RJK, Winarni D, Punnapayak H, Darmanto W. Antioxidant Potency of Okra (Abelmoschus esculentus Moench) Pods Extract on SOD Level and Tissue Glucose Tolerance in Diabetic Mice. Res J Pharm Technol. 12(12): 5683. DOI: 10.5958/0974-360X.2019.00983.1

23. Husen SA, Setyawan MF, Syadzha MF, Susilo RJK, Hayaza S, Ansori ANM, Alamsjah MA, Ilmi ZN, Wulandari PAC, Pudjiastuti P, Awang P, Winarni D. A Novel Therapeutic effects of Sargassum ilicifolium Alginate and Okra (Abelmoschus esculentus) Pods extracts on Open wound healing process in Diabetic Mice. Research J. Pharm. and Tech 2020; 13(6): 2764-2770. DOI: 10.5958/0974-360X.2020.00491.6

24. Kharisma VD, Kharisma SD, Ansori ANM, Kurniawan HP, Witaningrum AM, Fadholly A, Tacharina MR. Antiretroviral Effect Simulation from Black Tea (Camellia sinensis) via Dual Inhibitors Mechanism in HIV-1 and its Social Perspective in Indonesia. Res J Pharm Technol. 2021; 14(1): 455-460. DOI: 10.5958/0974-360X.2021.00083.4

25. Fadholly A, Ansori ANM, Kharisma VD, Rahmahani J, Tacharina MR. Immunobioinformatics of Rabies Virus in Various Countries of Asia: Glycoprotein Gene. Res J Pharm Technol. 2021; 14(2): 883-886. DOI: 10.5958/0974-360X.2021.00157.8

26. Ansori ANM, Fadholly A, Proboningrat A, Hayaza S, Susilo RJK, Naw SW, Posa GAV, Yusrizal YF, Sibero MT, Sucipto TH, Soegijanto S. In vitro antiviral activity of Pinus merkusii (Pinaceae) stem bark and cone against dengue virus type-2 (DENV-2). Res J Pharm Technol. 2021; 14(7): 3705-8. DOI: 10.52711/0974-360X.2021.00641

27. Ansori ANM, Kharisma VD, Fadholly A, Tacharina MR, Antonius Y, Parikesit AA. Severe Acute Respiratory Syndrome Coronavirus-2 Emergence and Its Treatment with Alternative Medicines: A Review. Research Journal of Pharmacy and Technology 2021; 14(10): 5551-7. DOI: 10.52711/0974-360X.2021.00967

28. Husen SA, Ansori ANM, Hayaza S, Susilo RJK, Zuraidah AA, Winarni D, Punnapayak H, Darmanto W. Therapeutic Effect of Okra (Abelmoschus esculentus Moench) Pods Extract on Streptozotocin-Induced Type-2 Diabetic Mice. Res J Pharm Technol. 2019; 12(8): 3703-3708. DOI: 10.5958/0974-360X.2019.00633.4

29. Ansori ANM, Kharisma VD, Solikhah TI. Medicinal properties of Muntingia calabura L.: A Review. Res J Pharm Technol. 2021; 14(8):4509-2. DOI: 10.52711/0974-360X.2021.00784

30. Fadholly A, Ansori ANM, Sucipto TH. An overview of naringin: Potential anticancer compound of citrus fruits. Research Journal of Pharmacy and Technology. 2020; 13(11): 5613-5619. DOI: 10.5958/0974-360X.2020.00979.8

31. Proboningrat A, Kharisma VD, Ansori ANM, Rahmawati R, Fadholly A, Posa GAV, Sudjarwo SA, Rantam FA, Achmad AB. In silico Study of Natural inhibitors for Human papillomavirus-18 E6 protein. Res J Pharm Technol. 2022; 15(3): 1251-6. DOI: 10.52711/0974-360X.2022.00209

32. Ramadhani NF, Nugraha AP, Ihsan IS, Agung YA, Rantam FA, Ernawati DS et al. Gingival medicinal signaling cells conditioned medium effect on the osteoclast and osteoblast number in lipopolysaccharide-induced calvaria bone resorption in wistar rats’ (Rattus novergicus). Research Journal of Pharmacy and Technology. 2021; 14(10): 5232-5237. DOI: 10.52711/0974-360X.2021.00911

33. Kharisma VD, Ansori ANM, Jakhmola V, Rizky WC, Widyananda MH, Probojati RT, Murtadlo AAA, Rebezov M, Scherbakov P, Burkov P, Matrosova Y, Romanov A, Sihombing MAEM, Antonius Y, Zainul R. Multi-strain human papillomavirus (HPV) vaccine innovation via computational study: A mini review. Res J Pharm Technol. 2022; 15(8): 3802-7. DOI: 10.52711/0974-360X.2022.00638

34. Fahmi M, Kharisma VD, Ansori ANM, Ito M. Retrieval and Investigation of Data on SARS-CoV-2 and COVID-19 Using Bioinformatics Approach. Adv Exp Med Biol. 2021; 1318: 839-857. DOI: 10.1007/978-3-030-63761-3_47

35. Kharisma VD, Probojati RT, Murtadlo AAA, Ansori ANM, Antonius Y, Tamam MB. Revealing Potency of Bioactive Compounds as Inhibitor of Dengue Virus (DENV) NS2B/NS3 Protease from Sweet Potato (Ipomoea batatas L.) Leaves. Indian J Forensic Med Toxicol. 2020; 15(1): 1627–1632. DOI: 10.37506/ijfmt.v15i1.13644

36. Husen SA, Winarni D, Salamun, Ansori ANM, Susilo RJK, Hayaza S. Hepatoprotective Effect of Gamma-mangostin for Amelioration of Impaired Liver Structure and Function in Streptozotocin-induced Diabetic Mice. IOP Conference Series: Earth and Environmental Science. 2019; 217(1): 012031. DOI: 10.1088/1755-1315/217/1/012031

37. Turista DDR, Islamy A, Kharisma VD, Ansori ANM. Distribution of COVID-19 and Phylogenetic Tree Construction of SARS-CoV-2 in Indonesia. J Pure Appl Microbiol. 2020; 14: 1035-1042. DOI: 10.22207/JPAM.14.SPL1.42

38. Kharisma VD, Widyananda MH, Ansori ANM, Nege AS, Naw SW, Nugraha AP Tea catechin as antiviral agent via apoptosis agonist and triple inhibitor mechanism against HIV-1 infection: A bioinformatics approach. J Pharm Pharmacogn Res. 9(4): 435-445.

39. Kharisma VD, Ansori ANM, Nugraha AP. Computational study of ginger (Zingiber Officinale) as E6 inhibitor in human papillomavirus type 16 (Hpv-16) infection. Biochemical and Cellular Archives. 2020; 20: 3155-3159. DOI: 10.35124/bca.2020.20.S1.3155

40. Ansori  ANM, Kharishma VD, Muttaqin SS, Antonius Y, Parikesit AA. Genetic Variant of SARS-CoV-2 Isolates in Indonesia: Spike Glycoprotein Gene. J Pure Appl Microbiol. 2020; 14: 971-978. DOI: 10.22207/JPAM.14.SPL1.35

41. Widyananda MH, Pratama SK, Samoedra RS, Sari FN, Kharisma VD, Ansori ANM, Antonius Y. Molecular docking study of sea urchin (Arbacia lixula) peptides as multi-target inhibitor for non-small cell lung cancer (NSCLC) associated proteins. J Pharm Pharmacogn Res. 2021; 9(4): 484–496.

42. Kharisma VD, Ansori ANM. Construction of Epitope-Based Peptide Vaccine Against SARS-CoV-2: Immunoinformatics Study. J Pure Appl Microbiol. 2020; 14: 999-1005. DOI: 10.22207/JPAM.14.SPL1.38

43. Kharisma VD, Ansori ANM, Widyananda MH, Utami SL, Nugraha AP. Molecular simulation: The potency of conserved region on E6 HPV-16 as a binding target of black tea compounds against cervical cancer. Biochemical and Cellular Archives. 2020; 20: 2795-2802. DOI: 10.35124/bca.2020.20.S1.2795

44. Kharisma VD, Agatha A, Ansori ANM, Widyananda MH, Rizky WC, Dings TGA, Derkho M, Lykasova I, Antonius Y, Rosadi I, Zainul R. Herbal combination from Moringa oleifera Lam. and Curcuma longa L. as SARS-CoV-2 antiviral via dual inhibitor pathway: A viroinformatics approach. J Pharm Pharmacogn Res. 2022; 10(1): 138-146. DOI: 10.56499/jppres21.1174_10.1.138

45. Khairullah AR, Solikhah TI, Ansori ANM, Hanisia RH, Puspitarani GA, Fadholly A, Ramandinianto SC. Medicinal importance of Kaempferia galanga L. (Zingiberaceae): A comprehensive review. J Herbmed Pharmacol. 2021; 10: 281-288. DOI: 10.34172/jhp.2021.32

46. Husen SA, Syadzha MF, Setyawan MF, Pudjiastuti P, Ansori ANM, Susilo RJK et al. Evaluation of the combination of sargassum duplicatum, sargassum ilicifolium, abelmoschus esculentus, and garcinia mangostana extracts for open wound healing in diabetic mice. Systematic Reviews in Pharmacy. 2020; 11(9): 888-892. DOI: 10.31838/srp.2020.9.129

47. Wijaya RM, Hafidzhah MA, Kharisma VD, Ansori ANM, Parikesit AP. COVID-19 In Silico Drug with Zingiber officinale Natural Product Compound Library Targeting the Mpro Protein. Makara J Sci. 2021; 25(3): 5. DOI: 10.7454/mss.v25i3.1244

48. Ansori ANM, Fadholly A, Kharisma VD, Nugraha AP. Therapeutic potential of avian paramyxovirus serotype 1 for cancer therapy. Biochemical and Cellular Archives. 2020;20:2827-2832. DOI: 10.35124/bca.2020.20.S1.2827

49. Prahasanti C, Nugraha AP, Kharisma VD, Ansori ANM, Ridwan RD, Putri TPS et al. Un enfoque bioinformático de la exploración con compuestos de hidroxiapatita y polimetilmetacrilato como biomaterial de implantes dentales. Journal of Pharmacy and Pharmacognosy Research. 2021; 9(5): 746-754.

50. Kharisma VD, Ansori ANM, Fadholly A, Sucipto TH. Molecular mechanism of caffeine-aspirin interaction in kopi balur 1 as anti-inflammatory agent: A computational study. Indian Journal of Forensic Medicine and Toxicology. 2020; 14(4): 4040-4046. DOI: 10.37506/ijfmt.v14i4.12274

51. Kharisma VD, Widodo N, Ansori ANM, Nugraha AP. A vaccine candidate of zika virus (ZIKV) from polyvalent conserved b-cell epitope on viral glycoprotein: In silico approach. Biochemical and Cellular Archives. 2020; 20: 2785-2793. DOI: 10.35124/bca.2020.20.S1.2785

52. Ansori ANM, Kharisma VD, Nugraha AP. Phylogenetic and pathotypic characterization of avian paramyxovirus serotype 1 (APMV-1) in Indonesia. Biochemical and Cellular Archives. 2020; 20: 3023-3027. https://doi.org/10.35124/bca.2020.20.S1.3023

53. Padmi H, Kharisma VD, Ansori ANM, Sibero MT, Widyananda MH, Ullah E, Gumenyuk O, Chylichcova S, Bratishko N, Prasedya ES, Sucipto TH, Zainul R. Macroalgae Bioactive Compounds for the Potential Antiviral of SARS-CoV-2: An In Silico Study. Journal of Pure and Applied Microbiology. 2022; 16(2): 1018-1027. DOI: 10.22207/JPAM.16.2.26

54. Antonius Y, Kharisma VD, Widyananda MH, Ansori ANM, Trinugroho JP, Ullah ME, Naw SW, Jakhmola V, Wahjudi M. Prediction of Aflatoxin-B1 (AFB1) Molecular Mechanism Network and Interaction to Oncoproteins Growth Factor in Hepatocellular Carcinoma. J Pure Appl Microbiol. 2022; 16(3): 1844-1854. doi: 10.22207/JPAM.16.3.29

55. Dibha AF, Wahyuningsih S, Ansori ANM, Kharisma VD, Widyananda MH, Parikesit AA, Sibero MT, Probojati RT, Murtadlo AAA, Trinugroho JP, Sucipto TH, Turista DDR, Rosadi I, Ullah ME, Jakhmola V, Zainul R. Utilization of Secondary Metabolites in Algae Kappaphycus alvarezii as a Breast Cancer Drug with a Computational Method. Pharmacognosy Journal. 2022; 14(3): 536-543. DOI: 10.5530/pj.2022.14.68

56. Aini NS, Ansori ANM, Kharisma VD, Syadzha MF, Widyananda MH, Murtadlo AA, et al. Potential Roles of Purslane (Portulaca oleracea L.) as Antimetabolic Syndrome: A Review. Pharmacognosy Journal. 2022; 14(3): 710-714. DOI: 10.5530/pj.2022.14.90

57. Listiyani P, Kharisma VD, Ansori AN, Widyananda MH, Probojati RT, Murtadlo AA, et al. In Silico Phytochemical Compounds Screening of Allium sativum Targeting the Mpro of SARS-CoV-2. Pharmacognosy Journal. 2022; 14(3): 604-609. DOI: 10.5530/pj.2022.14.78

58. Aini NS, Kharisma VD, Widyananda MH, Murtadlo AA, Probojati RT, Turista DD, et al. In Silico Screening of Bioactive Compounds from Syzygium cumini L. and Moringa oleifera L. Against SARS-CoV-2 via Tetra Inhibitors. Pharmacognosy Journal. 2022;14(4): 267-272. DOI: 10.5530/pj.2022.14.95

59. Aini NS, Kharisma VD, Widyananda MH, Murtadlo AA, Probojati RT, Turista DD, et al. Bioactive Compounds from Purslane (Portulaca oleracea L.) and Star Anise (Illicium verum Hook) as SARS-CoV-2 Antiviral Agent via Dual Inhibitor Mechanism: In Silico Approach. Pharmacognosy Journal. 2022; 14(4): 352-357. DOI: 10.5530/pj.2022.14.106

60. Ansori ANM, Fadholly A, Proboningrat A, Antonius Y, Hayaza S, Susilo RJ, Inayatillah B, Sibero MT, Naw SW, Posa GAV, Sucipto TH, Soegijanto S. Novel Antiviral Investigation of Annona squamosa Leaf Extract against the Dengue Virus Type-2: In vitro Study. Phcog J. 2021; 13(2): 456-462. DOI: 10.5530/pj.2021.13.58

61. Ansori AN, Kharisma VD, Parikesit AA, Dian FA, Probojati RT, Rebezov M, Scherbakov P, Burkov P, Zhdanova G, Mikhalev A, Antonius Y, Pratama MRF, Sumantri NI, Sucipto TH, Zainul R. Bioactive Compounds from Mangosteen (Garcinia mangostana L.) as an Antiviral Agent via Dual Inhibitor Mechanism against SARS-CoV- 2: An In Silico Approach. Phcog J. 2022; 14(1): 85-90. DOI: 10.5530/pj.2022.14.12

62. Wicaksono A, Kharisma VD, Parikesit AA. New Perspectives on Reverse Translation: Brief History and Updates, Universitas Scientiarum. 2023l 28(1): 1–20, 2. DOI: 10.11144/Javeriana.SC281.npor

Received on 18.04.2023            Modified on 06.06.2023

Accepted on 12.07.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(4):1777-1783.

DOI: 10.52711/0974-360X.2024.00282