Research Journal of Pharmacy and Technology

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In Silico Study of Natural Inhibitors for Human Papillomavirus-18 E6 Protein


Affiliations
1 Doctoral Program in Veterinary Science, Faculty of Veterinary Medicine, Universitas Airlangga, 60115, Surabaya,, Indonesia
2 Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Brawijaya, 65145, Malang,, Indonesia
3 Department of Chemistry, Faculty of Health Sciences, Muhammadiyah University of Surabaya, 60113, Surabaya,, Indonesia
4 School of Environmental Science and Management, University of the Philippines Los Baños, Los Baños,, Philippines
5 Department of Pharmacology, Faculty of Veterinary Medicine, Universitas Airlangga, 60115, Surabaya,, Indonesia
6 Research Center for Vaccine Technology and Development, Institute of Tropical Disease, Universitas Airlangga, 60115, Surabaya,, Indonesia
7 Department of Health, Faculty of Vocational Studies, Universitas Airlangga, 60115, Surabaya,, Indonesia
     

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Globally, the leading cause of death from cancer in women is infection with the human papillomavirus (HPV). This calls for imperative actions to explore anticancer drugs against this threatening viral infection, in which case, natural ingredients are presumed to be a promising source. Several studies show that plant-origin compounds such as allicin, apigenin, capsaicin, cyanidin, fisetin, genistein, laricitrin, naringenin, piperine, and syringetin have demonstrated therapeutic effects against several cancer types. In this study, the interaction mechanism of these compounds with HPV-18 E6 oncoprotein, that is known to downregulate tumor suppressor p53, was predicted using an in silico approach. Molecular docking simulations of natural ligands and E6 protein were performe, followed by chemical interaction analysis and 3D molecular visualization. Results indicated that fisetin is the best natural inhibitor as it has the lowest binding energy. It is highly recommended that the results of this study be used as a reference in designing anticancer drugs in vitro and in vivo.

Keywords

HPV, E6, cervical cancer, inhibitors, virtual screening.
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  • Chang Y. Moore PS. Weiss RA. Human oncogenic viruses: nature and discovery. Philosophical transactions of the Royal Society of London. Series B, Biological Sciences. 2017; 372. doi.org/10.1098/rstb.2016.0264

  • Nabati F. Moradi M. Mohabatkar H. In silico analyzing the molecular interactions of plant-derived inhibitors against E6AP, p53, and c-Myc binding sites of HPV type 16 E6 oncoprotein. Molecular Biology Research Communications. 2020; 9(2): 71-82. doi.org/10.22099/mbrc.2020.36522.1483

  • Johari B. Ebrahimi-Rad M. Maghsood F. Lotfinia M. Saltanatpouri Z. Teimoori-Toolabi L. Sharifzadeh Z. Karimipoor M. Kadivar M. Myc decoy oligodeoxynucleotide inhibits growth and modulates differentiation of mouse embryonic stem cells as a model of cancer stem cells. Anti-cancer Agents in Medicinal Chemistry. 2017; 17: 1786-1795. doi.org/10.2174/1871521409666170412142507

  • Johari B. Zargan J. Simultaneous targeted inhibition of Sox2‐Oct4 transcription factors using decoy oligodeoxynucleotides to repress stemness properties in mouse embryonic stem cells. Cell Biology International. 2017; 41: 1335-1344. doi.org/10.1002/cbin.10847

  • Tambunan USF. Parikesit AA. HPV Bioinformatics: In silico detection, drug design and prevention agent development. In: Topics on Cervical Cancer With an Advocacy for Prevention. InTech. 2012 doi.org/10.5772/27456

  • Kumar S. Jena L. Mohod K. Daf S. Varma AK. Virtual screening for potential inhibitors of high-risk human papillomavirus 16 E6 protein. Interdisciplinary Sciences, Computational Life Sciences. 2015; 1-7. doi:10.1007/s12539-013-0213-6

  • Park MS. Chang BS. Ultrastructural characteristics of hpv in women’s vaginal cells. Research Journal of Pharmacy and Technology. 2019; 12(9): 4305-4309. doi.org/10.5958/0974-360X.2019.00740.6

  • Kumar S. Jena L. Sahoo M. Kakde M. Daf S. Varma AK. In silico docking to explicate interface between plant-originated inhibitors and E6 oncogenic protein of highly threatening human papillomavirus 18. Genomics & Informatics. 2015; 13(2): 60-67. doi.org/10.5808/GI.2015.13.2.60

  • Merkhofer C. Maslow J. Human Papilloma virus (HPV) infection and non-cervical oncogenic disease states. Virology & Mycology. 2015; 4: 2. doi.org/10.4172/2161-0517.1000144

  • Bharatha Soruba Rani S. HPV infection and cervical cancer. International Journal of Nursing Education and Research. 2015; 3(2): 229-231. doi.org/10.5958/2231–5713

  • Fernandes JV. Fernandes TAAM. Human papillomavirus: biology and pathogenesis. In: Human papillomavirus and related diseases – from bench to bedside – a clinical perspective. InTech. 2012; 1-5. doi.org/10.5772/27154

  • Pinidis P. Tsikouras P. Iatrakis G. Zervoudis S. Koukouli Z. Bothou A. Galazios G. Vladareanu S. Human papilloma virus’ life cycle and carcinogenesis. MAEDICA – a Journal of Clinical Medicine. 2016; 11(5): 48-54. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394500

  • de Sanjose S. Brotons M. Pavon MA. The natural history of human papillomavirus infection. Best practice & research. Clinical Obstetrics & Gynaecology. 2018; 47: 2-13. doi.org/10.1016/j.bpobgyn.2017.08.015

  • 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(1): 2795-2802. doi.org/10.35124/bca.2020.20.S1.2795

  • Messa L. Celegato M. Bertagnin C. Mercorelli B. Nannetti G. Palù G. Loregian A. A quantitative LumiFluo assay to test inhibitory compounds blocking p53 degradation induced by human papillomavirus oncoprotein E6 in living cells. Scientific Reports. 2018; 8: 1-11. doi.org/10.1038/s41598-018-24470-4

  • Marimuthu N. Viswanathan T. Radha M. Suganya J. Computational Screening of the phytocompounds from the plant Ballota nigra Linn against the human papillomavirus (HPV) E6. Research Journal of Pharmacy and Technology. 2017; 10(9): 3095-3097. doi.org/10.5958/0974-360X.2017.00549.2

  • Proboningrat A. Ansori ANM. Fadholly A. Putri N. Kusala MKJ. Achmad AB. First report on the cytotoxicity of Pinus merkusii bark extract in WiDr, a human colon carcinoma cell line. Research Journal of Pharmacy and Technology. 2021; 14(3): 1685-1688. doi.org/10.5958/0974-360X.2021.00299.7

  • Zhang Q. Yang D. Allicin suppresses the migration and invasion in cervical cancer cells mainly by inhibiting NRF2. Experimental and Therapeutic Medicine. 2019; 17: 1523-1528. doi.org/10.3892/etm.2018.7104

  • Imran M. Gondal TA. Atif M. Shahbaz M. Qaisarani TB. Mughal MH. Salehi B. Martorell M. Rad JS. Apigenin as an anticancer agent. Phytotherapy Research. 2020; 1-17. doi.org/10.1002/ptr.6647

  • Zhang S. Wang D. Huang J. Hu Y. Xu Y. Application of capsaicin as a potential new therapeutic drug in human cancers Journal of Clinical Pharmacy and Therapeutics. 2019; 45: 16-28. doi.org/10.1111/jcpt.13039

  • Sorrenti V. Vanella L. Acquaviva R. Cardile V. Giofre S. Giacomo CD. Cyanidin induces apoptosis and differentiation in prostate cancer cells. International Journal of Oncology. 2015; 47: 1303-1310. doi.org/10.3892/ijo.2015.3130

  • Kumar R. Kumar R. Khursheed R. Kapoor B. Sharma N. Khurana S. Khurana N. Singh SK. Vyas M. Development and validation of uv spectroscopic method for estimation of fisetin in self nanoemulsifying drug delivery system. Research Journal of Pharmacy and Technology. 2020; 13(3): 1179-1182. doi.org/10.5958/0974-360X.2020.00217.6

  • Imran M. Saeed F. Gilani SA. Shariati MA. Imran A. Afzaal M. Atif M. Tufail T. Anjum FM. Fisetin: An anticancer perspective. Food Science & Nutrition. 2020; 9(1): 3-16. doi.org/10.1002/fsn3.1872

  • Tuli HS. Tuorkey MJ. Thakral F. Sak K. Kumar M. Sharma AK. Sharma U. Jain A. Aggarwal V. Bishayee A. Molecular mechanisms of action of genistein in cancer: recent advances. Frontiers in Pharmacology. 2019; 10: 1-16. doi.org/10.3389/fphar.2019.01336

  • Chang WA. Hung JY. Jian SF. Lin YS. Wu CY. Hsu YL. Kuo PL. Laricitrin ameliorates lung cancer-mediated dendritic cell suppression by inhibiting signal transducer and activator of transcription 3. Oncotarget. 2016; 7(51): 85220-85234. doi.org/10.18632/oncotarget.13240

  • 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.org/10.5958/0974-360X.2020.00979.8

  • Rodriguez OPM. Torres AG. Salas LMA. Sanchez HH. Perez BEG. Bonilla MRT. Flores MEJ. Effect of naringenin and its combination with cisplatin in cell death, proliferation and invasion of cervical cancer spheroids. RSC Advances. 2020; 11: 129-141. doi.org/10.1039/D0RA07309A

  • El-Aasr M. Kabbash A. El-Seoud KAA. Al-Madboly LA. Ikeda T. Antimicrobial and immunomodulatory activities of flavonol glycosides isolated from Atriplex halimus L. herb. Journal of Pharmaceutical Sciences and Research. 2016; 8(10): 1159-1168. Retrieved from https://www.jpsr.pharmainfo.in/issue.php?page=86

  • Sindhu TJ. Arathi KN. Akhilesh KJ. Anju J. Binsiya KP. Thomas B. Wilson E. Antiviral screening of clerodol derivatives as COV 2 main protease inhibitor in novel corona virus disease: In silico approaches. Asian Journal of Pharmacy and Technology. 2020; 10(2): 60-64. doi.org/10.5958/2231-5713.2020.00012.4

  • Kharisma VD. Syafrudin S. Septiadi L. Prediction of novel bioactive compound from Z. officinale as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 through computational study. Bioinformatics and Biomedical Research Journal. 2018; 1(2): 49-55. doi.org/10.11594/bbrj.01.02.05

  • Ray NM. Singh R. Singh J. Bhati S. Kaushik V. Computational screening of thiohydantoin derivatives for antitumor activity. Research Journal of Pharmacy and Technology. 2020; 13(2): 795-800. doi.org/10.5958/0974-360X.2020.00150.X

  • Daina A. Michielin O. Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017; 7: 42717. doi.org/10.1038/srep42717

  • 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(1): 3155-3159. doi.org/10.35124/bca.2020.20.S1.3155

  • Purnama ER. Kharisma VD. Epitope mapping of capsid protein L1 from human papillomavirus to development cervical cancer vaccine through computational study. Journal of Physics: Conference Series. 2018; 1108: 1-6. doi.org/10.1088/1742-6596/1108/1/012096

  • Adianingsih OR. Kharisma VD. Study of B cell epitope conserved region of the Zika virus envelope glycoprotein to develop multi-strain vaccine. Journal of Applied Pharmaceutical Science. 2019: 9(1): 98-103. doi.org/10.7324/JAPS.2019.90114

  • Fernandes TB. Segretti MCF. Polli MC. Filho RP. Analysis of the applicability and use of Lipinski`s rule for central nervous system drugs. Letters in Drug Design & Discovery. 2016; 13: 1-8. doi.org/10.2174/1570180813666160622092839

  • Buvana C. Sumathy A. Sukumar M. In silico Identification of potential xanthine oxidase inhibitors for the treatment of gout and cardiovascular disease. Asian Journal of Pharmacy and Technology. 2013; 6(11): 1049-1053. doi.org/10.5958/0974-4150

  • Lipinski CA. Lombardo F. Dominy BW. Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 2001; 46(1-3): 3-26. doi.org/10.1016/s0169-409x(00)00129-0

  • 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. Research Journal of Pharmacy and Technology. 2021; 14(1): 455-460. doi.org/10.5958/0974-360X.2021.00083.4

  • Sukmanadi M. Sudjarwo SA. Effendi MH. Molecular mechanism of capsaicin from (Capsicum annuum L.) on expression of MAPK1 and AKT1 protein as candidate of anticancer drugs: In silico study. Pharmacognosy Journal. 2020; 12(4): 916-919. doi.org/10.5530/pj.2020.12.130

  • 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. Retrieved from https://jppres.com/jppres/sea-urchin-peptides-as-multi-target-inhibitor-of-nsclc

  • Hassan NM. Alhossary AA. Mu Y. Kwoh CK. Protein ligand blind docking using QuickVina-W with inter-process spatio-temporal integration. Scientific Reports. 2017; 7(1): 15451. doi.org/10.1038/s41598-017-15571-7

  • Ramírez D. Caballero J. Is it reliable to use common molecular docking methods for comparing the binding affinities of enantiomer pairs for their protein target? International Journal of Molecular Sciences. 2016; 17(4): 525. doi.org/10.3390/ijms17040525

  • Durell SR. Ben-Naim A. Hydrophobic-hydrophilic forces in protein folding. Biopolymers. 2017: 107: 8. doi.org/10.1002/bip.23020


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  • In Silico Study of Natural Inhibitors for Human Papillomavirus-18 E6 Protein

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Authors

Annise Proboningrat
Doctoral Program in Veterinary Science, Faculty of Veterinary Medicine, Universitas Airlangga, 60115, Surabaya,, Indonesia
Viol Dhea Kharisma
Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Brawijaya, 65145, Malang,, Indonesia
Arif Nur Muhammad Ansori
Doctoral Program in Veterinary Science, Faculty of Veterinary Medicine, Universitas Airlangga, 60115, Surabaya,, Indonesia
Rinza Rahmawati
Department of Chemistry, Faculty of Health Sciences, Muhammadiyah University of Surabaya, 60113, Surabaya,, Indonesia
Amaq Fadholly
Doctoral Program in Veterinary Science, Faculty of Veterinary Medicine, Universitas Airlangga, 60115, Surabaya,, Indonesia
Gabrielle Ann Villar Posa
School of Environmental Science and Management, University of the Philippines Los Baños, Los Baños,, Philippines
Sri Agus Sudjarwo
Department of Pharmacology, Faculty of Veterinary Medicine, Universitas Airlangga, 60115, Surabaya,, Indonesia
Fedik Abdul Rantam
Research Center for Vaccine Technology and Development, Institute of Tropical Disease, Universitas Airlangga, 60115, Surabaya,, Indonesia
Agung Budianto Achmad
Department of Health, Faculty of Vocational Studies, Universitas Airlangga, 60115, Surabaya,, Indonesia

Abstract


Globally, the leading cause of death from cancer in women is infection with the human papillomavirus (HPV). This calls for imperative actions to explore anticancer drugs against this threatening viral infection, in which case, natural ingredients are presumed to be a promising source. Several studies show that plant-origin compounds such as allicin, apigenin, capsaicin, cyanidin, fisetin, genistein, laricitrin, naringenin, piperine, and syringetin have demonstrated therapeutic effects against several cancer types. In this study, the interaction mechanism of these compounds with HPV-18 E6 oncoprotein, that is known to downregulate tumor suppressor p53, was predicted using an in silico approach. Molecular docking simulations of natural ligands and E6 protein were performe, followed by chemical interaction analysis and 3D molecular visualization. Results indicated that fisetin is the best natural inhibitor as it has the lowest binding energy. It is highly recommended that the results of this study be used as a reference in designing anticancer drugs in vitro and in vivo.

Keywords


HPV, E6, cervical cancer, inhibitors, virtual screening.

References