In silico Analysis of Natural Inhibitors against HPV E6 Protein


Cite item

Full Text

Abstract

Background:Drug re-purposing is one of the cost-effective methods to establish novel therapeutics against many diseases. Established natural products are collected from databases and used to potentially screen them against HPV E6 protein, a critical viral protein.

Objective:This study aims to design potential small molecule inhibitors against HPV E6 protein using structure-based approaches. Ten natural anti-cancerous compounds (Apigenin, Baicalein, Baicalin, Ponicidin, Oridonin, Lovastatin, Triterpenoid, Narirutin, Rosmarinic Acid, and Xanthone) were selected by review of the literature.

Methods:These compounds were screened using Lipinski Rule of Five. Out of ten compounds, seven were found to satisfy Rule of five. Docking of these seven compounds was carried out using AutoDock software and corresponding Molecular Dynamics Simulations were performed by GROMACS.

Results:Among the seven compounds docked with the E6 target protein, six compounds showed lesser binding energy than the reference compound, Luteolin. The three-dimensional structures of E6 protein and the corresponding ligand complexes were visualised and analysed using PyMOL whereas the two-dimensional images of protein-ligand interactions were obtained by LigPlot+ software to study the specific interactions. ADME analysis using SwissADME software revealed that all the compounds except Rosmarinic acid have good gastrointestinal absorption and solubility characteristics while Xanthone and Lovastatin showed blood brain barrier penetration properties. Considering the binding energy and ADME analysis, Apigenin and Ponicidin are found to be most suitable for de novo designing of potential inhibitors against the HPV16 E6 protein.

Conclusion:Further, synthesis and characterization of these potential HPV16 E6 inhibitors will be carried out and their functional evaluation using cell culture-based assays will be undertaken.

About the authors

Vemula Vani

Department of Microbiology, MS Ramaiah College of Arts, Science and Commerce,

Email: info@benthamscience.net

Snehalatha Venkateshappa

Department of Microbiology, MS Ramaiah College of Arts, Science and Commerce

Email: info@benthamscience.net

Rachel Nishitha

Department of Microbiology,, MS Ramaiah College of Arts Science & Commerce

Email: info@benthamscience.net

Hima Shashidhar

Department of Microbiology,, MS Ramaiah College of Arts Science & Commerce

Email: info@benthamscience.net

Arpitha Hegde

Department of Microbiology,, MS Ramaiah College of Arts Science & Commerce

Email: info@benthamscience.net

Manikandan Alagumuthu

Department of Microbiology,, MS Ramaiah College of Arts Science & Commerce

Author for correspondence.
Email: info@benthamscience.net

References

  1. Allison, D.B.; Maleki, Z. HPV-related head and neck squamous cell carcinoma: An update and review. J. Am. Soc. Cytopathol., 2016, 5(4), 203-215. doi: 10.1016/j.jasc.2015.12.001 PMID: 31042510
  2. Kombe Kombe, A.J.; Li, B.; Zahid, A.; Mengist, H.M.; Bounda, G.A.; Zhou, Y.; Jin, T. Epidemiology and burden of human papillomavirus and related diseases, molecular pathogenesis, and vaccine evaluation. Front. Public Health, 2021, 8, 552028. doi: 10.3389/fpubh.2020.552028 PMID: 33553082
  3. Cheng, L.; Wang, Y.; Du, J. Human papillomavirus vaccines: An updated review. Vaccines, 2020, 8(3), 391. doi: 10.3390/vaccines8030391 PMID: 32708759
  4. Akhatova, A.; Azizan, A.; Atageldiyeva, K.; Ashimkhanova, A.; Marat, A.; Iztleuov, Y.; Suleimenova, A.; Shamkeeva, S.; Aimagambetova, G. Prophylactic human papillomavirus vaccination: From the origin to the current state. Vaccines, 2022, 10(11), 1912. doi: 10.3390/vaccines10111912 PMID: 36423008
  5. Hampson, L.; Martin-Hirsch, P.; Hampson, I.N. An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia. Expert Opin. Investig. Drugs, 2015, 24(12), 1529-1537. doi: 10.1517/13543784.2015.1099628 PMID: 26457651
  6. Mittal, S.; Banks, L. Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation. Mutat. Res. Rev. Mutat. Res., 2017, 772, 23-35. doi: 10.1016/j.mrrev.2016.08.001 PMID: 28528687
  7. Pal, A.; Kundu, R. Human papillomavirus E6 and E7: The cervical cancer hallmarks and targets for therapy. Front. Microbiol., 2020, 10, 3116. doi: 10.3389/fmicb.2019.03116 PMID: 32038557
  8. Howie, H.L.; Katzenellenbogen, R.A.; Galloway, D.A. Papillomavirus E6 proteins. Virology, 2009, 384(2), 324-334. doi: 10.1016/j.virol.2008.11.017 PMID: 19081593
  9. Martinez-Zapien, D.; Ruiz, F.X.; Poirson, J.; Mitschler, A.; Ramirez, J.; Forster, A.; Cousido-Siah, A.; Masson, M.; Pol, S.V.; Podjarny, A.; Travé, G.; Zanier, K. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature, 2016, 529(7587), 541-545. doi: 10.1038/nature16481 PMID: 26789255
  10. Scheffner, M.; Münger, K.; Byrne, J.C.; Howley, P.M. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc. Natl. Acad. Sci. USA, 1991, 88(13), 5523-5527. doi: 10.1073/pnas.88.13.5523 PMID: 1648218
  11. Zanier, K.; Charbonnier, S.; Sidi, A.O.M.O.; McEwen, A.G.; Ferrario, M.G.; Poussin-Courmontagne, P.; Cura, V.; Brimer, N.; Babah, K.O.; Ansari, T.; Muller, I.; Stote, R.H.; Cavarelli, J.; Vande Pol, S.; Travé, G. Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins. Science, 2013, 339(6120), 694-698. doi: 10.1126/science.1229934 PMID: 23393263
  12. Malecka, K.A.; Fera, D.; Schultz, D.C.; Hodawadekar, S.; Reichman, M.; Donover, P.S.; Murphy, M.E.; Marmorstein, R. Identification and characterization of small molecule human papillomavirus E6 inhibitors. ACS Chem. Biol., 2014, 9(7), 1603-1612. doi: 10.1021/cb500229d PMID: 24854633
  13. Zanier, K.; Stutz, C.; Kintscher, S.; Reinz, E.; Sehr, P.; Bulkescher, J.; Hoppe-Seyler, K.; Travé, G.; Hoppe-Seyler, F. The E6AP binding pocket of the HPV16 E6 oncoprotein provides a docking site for a small inhibitory peptide unrelated to E6AP, indicating druggability of E6. PLoS One, 2014, 9(11), e112514. doi: 10.1371/journal.pone.0112514 PMID: 25383876
  14. Donà, M.G.; Di Bonito, P.; Chiantore, M.V.; Amici, C.; Accardi, L. Targeting human papillomavirus-associated cancer by oncoprotein-specific recombinant antibodies. Int. J. Mol. Sci., 2021, 22(17), 9143. doi: 10.3390/ijms22179143 PMID: 34502053
  15. Baleja, J.D.; Cherry, J.J.; Liu, Z.; Gao, H.; Nicklaus, M.C.; Voigt, J.H.; Chen, J.J.; Androphy, E.J. Identification of inhibitors to papillomavirus type 16 E6 protein based on three-dimensional structures of interacting proteins. Antiviral Res., 2006, 72(1), 49-59. doi: 10.1016/j.antiviral.2006.03.014 PMID: 16690141
  16. Cherry, J.J.; Rietz, A.; Malinkevich, A.; Liu, Y.; Xie, M.; Bartolowits, M.; Davisson, V.J.; Baleja, J.D.; Androphy, E.J. Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function. PLoS One, 2013, 8(12), e84506. doi: 10.1371/journal.pone.0084506 PMID: 24376816
  17. DiMasi, J.A.; Grabowski, H.G.; Hansen, R.W. Innovation in the pharmaceutical industry: New estimates of R&D costs. J. Health Econ., 2016, 47, 20-33. doi: 10.1016/j.jhealeco.2016.01.012 PMID: 26928437
  18. Murgueitio, M.S.; Bermudez, M.; Mortier, J.; Wolber, G. In silico virtual screening approaches for anti-viral drug discovery. Drug Discov. Today. Technol., 2012, 9(3), e219-e225. doi: 10.1016/j.ddtec.2012.07.009 PMID: 24990575
  19. Wang, H.; Oo Khor, T.; Shu, L.; Su, Z.Y.; Fuentes, F.; Lee, J.H.; Tony Kong, A-N. Plants vs. cancer: A review on natural phytochemicals in preventing and treating cancers and their druggability. Anticancer. Agents Med. Chem., 2012, 12(10), 1281-1305. doi: 10.2174/187152012803833026 PMID: 22583408
  20. Sagar, S.M. Natural health products that inhibit angiogenesis: A potential source for investigational new agents to treat cancer-Part 1. Current oncology, 2006, 13(1), 14-26.
  21. Lin, C.K.; Liu, S.T.; Chang, C.C.; Huang, S.M. Regulatory mechanisms of fluvastatin and lovastatin for the p21 induction in human cervical cancer HeLa cells. PLoS One, 2019, 14(4), e0214408. doi: 10.1371/journal.pone.0214408 PMID: 30939155
  22. Rawson, N.E.; Ho, C-T.; Li, S. Efficacious anti-cancer property of flavonoids from citrus peels. Food Sci. Hum. Wellness, 2014, 3(3-4), 104-109. doi: 10.1016/j.fshw.2014.11.001
  23. Vieira, L.M.M.; Kijjoa, A. Naturally-occurring xanthones: Recent developments. Curr. Med. Chem., 2005, 12(21), 2413-2446. doi: 10.2174/092986705774370682 PMID: 16250871
  24. Beutner, K.R.; Ferenczy, A. Therapeutic approaches to genital warts. Am. J. Med., 1997, 102(5A), 28-37. doi: 10.1016/S0002-9343(97)00181-2 PMID: 9217660
  25. Alagumuthu, M.; Muralidharan, V.P.; Andrew, M.; Ahmed, M.H.; Iyer, S.K.; Arumugam, S. Computational approaches to develop isoquinoline based antibiotics through DNA gyrase inhibition mechanisms unveiled through antibacterial evaluation and molecular docking. Mol. Inform., 2018, 37(12), 1800048. doi: 10.1002/minf.201800048 PMID: 30051592
  26. Alagumuthu, M.; Arumugam, S. Molecular docking, discovery, synthesis, and pharmacological properties of new 6-substituted-2-(3-phenoxyphenyl)-4-phenyl quinoline derivatives; an approach to developing potent DNA gyrase inhibitors/antibacterial agents. Bioorg. Med. Chem., 2017, 25(4), 1448-1455. doi: 10.1016/j.bmc.2017.01.007 PMID: 28094220
  27. Sanner, Michel F. A programming language for software integration and development. J. Mol. Graphics Mod., 1999, 57-61.
  28. Lilkova, E. The PyMOL Molecular Graphics System, Version 2.0 Schrodinger, LLC. 2015.
  29. Wallace, A.C.; Laskowski, R.A.; Thornton, J.M. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng. Des. Sel., 1995, 8(2), 127-134. doi: 10.1093/protein/8.2.127 PMID: 7630882
  30. Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 235-242.
  31. Jayaram, B.; Singh, T.; Mukherjee, G.; Mathur, A.; Shekhar, S.; Shekhar, V. Sanjeevini: A freely accessible web-server for target directed lead molecule discovery. BMC Bioinformatics, 2012, 13(Suppl. 17), S7. doi: 10.1186/1471-2105-13-S17-S7 PMID: 23282245
  32. Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341. doi: 10.1016/j.ddtec.2004.11.007 PMID: 24981612
  33. O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3(1), 33. doi: 10.1186/1758-2946-3-33 PMID: 21982300
  34. Alagumuthu, M.; Rajpoot, S.; Baig, M.S. Structure-based design of novel peptidomimetics targeting the SARS-CoV-2 spike protein. Cell. Mol. Bioeng., 2021, 14(2), 177-185. doi: 10.1007/s12195-020-00658-5 PMID: 33072222
  35. Oostenbrink, C.; Villa, A.; Mark, A.E.; Van Gunsteren, W.F. A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6. J. Comput. Chem., 2004, 25(13), 1656-1676. doi: 10.1002/jcc.20090 PMID: 15264259
  36. Stefl, P. What is log Pow? The O/W partition coefficient in SDSs. , 2017. Available From: https://www.gesi.de/en/blog/2017/02/06/what-is-log-pow-the-o-w-partition-coefficient-in-sdss/
  37. Fagerholm, U.; Hellberg, S.; Spjuth, O. Advances in predictions of oral bioavailability of candidate drugs in man with new machine learning methodology. Molecules, 2021, 26(9), 2572. doi: 10.3390/molecules26092572 PMID: 33925103
  38. Middha, S.K.; Goyal, A.K.; Faizan, S.A.; Sanghamitra, N.; Basistha, B.C.; Usha, T. In silico based combinatorial pharmacophore modelling and docking studies of GSK-3β and GK inhibitors of Hippophae. J. Biosci., 2013, 38(4), 805-814. doi: 10.1007/s12038-013-9367-y PMID: 24287660
  39. Negi, J.S.; Bisht, V.K.; Singh, P.; Rawat, M.S.M.; Joshi, G.P. Naturally occurring xanthones: chemistry and biology. J. Appl. Chem., 2013, 621459, 2013. doi: 10.1155/2013/621459

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2024 Bentham Science Publishers