Drug repurposing approach for the identification and designing of potential E6 inhibitors against cervical cancer: an in silico investigation
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Repurposing of ‘old’ drugs to treat both common and rare diseases has garnered huge attention of the researchers because of the high attrition rates and extortionate cost involved in new drug discovery. Almost in 100% of cases, high-risk HPV DNA has been found to be associated with cervical cancer. The viral E6 and E7 genes are regularly maintained and expressed in cervical cancer. So, the functional inhibition of E6 can be a promising therapeutic target for HPV-associated cervical cancer. In the present study, a five feature (AADRR) e-pharmacophore model was built based on amino acid residues reported by Zanier et al. and predicted by the Sitemap module of Maestro (Schrödinger). FDA-approved drugs library was screened employing the developed model and identified hits (based on phase screen score) were further put for docking and molecular dynamics (MD) simulations studies. The top two identified hits were ZINC000001543916 (valganciclovir; anti-viral drug) and ZINC000003795098 (cytarabine; anti-cancer drug). Incidentally, our target protein E6 can be classified under the field of tumour virology. Identified five hits are either purine or pyrimidine derivatives. We have also reported compound ASK4, a valganciclovir derivative as a potential E6 inhibitor. Molecular docking studies suggest that H-bond interaction with TYR32 and CYS51 amino acid residues is important for E6 inhibition. MD simulations studies indicated that the ligands might form stable complex with the E6 protein. All the designed compounds showed acceptable ADME profile. Further purine and pyrimidine scaffold can be used to design novel E6 inhibitors.
KeywordsDrug repurposing Cancer HPV e-Pharmacophore Virtual screening Molecular dynamics simulations
The authors are thankful to Manipal - Schrödinger Centre for Molecular Simulations, Manipal Academy of Higher Education and Manipal College of Pharmaceutical Sciences for providing necessary supports and facilities to carry out the present research work.
The authors are thankful to BioCARe, Department of Biotechnology, Government of India, New Delhi (Grant No. BT/PR18194/BIC/101/631/2016) for financial support.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.GLOBOCAN (2018) Cancer Today-IARC France http://www.gco.iarc.fr. Accessed 04 April 2019
- 9.Doorbar J, Griffin H (2007) Intrabody strategies for the treatment of human papillomavirus-associated disease. Expert Opin Biol Ther. https://doi.org/10.1517/147125188.8.131.527
- 12.Fehrmann F, Laimins LA (2003) Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation. Oncogene. https://doi.org/10.1038/sj.onc.1206554
- 13.Scheffner M, Whitaker NJ (2003) Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system. Semin Cancer Biol. https://doi.org/10.1016/S1044-579X(02)00100-1
- 14.Zanier K, Stutz C, Kintscher S, Reinz E, Sehr P, Bulkescher J, Hoppe-Seyler K, Travé G, Hoppe-Seyler F (2014) 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. https://doi.org/10.1371/journal.pone.0112514
- 18.Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (1996) Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 8(2):47–52Google Scholar
- 21.Heinrich MC, Joensuu H, Demetri GD, Corless CL, Apperley J, Fletcher JA, Soulieres D, Dirnhofer S, Harlow A, Town A (2008) Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res 14(9):2717–2725CrossRefGoogle Scholar
- 24.Sterling T, Irwin JJ (2015) ZINC 15 - ligand discovery for everyone. J Chem Inf Model. https://doi.org/10.1021/acs.jcim.5b00559
- 25.Schrödinger Release 2019-1: Maestro, Schrödinger, LLC, New York, NY, 2019Google Scholar
- 31.Bowers KJ, Chow DE, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD (2006) Scalable algorithms for molecular dynamics simulations on commodity clusters. In ACM/IEEE SC 2006 Conference (SC’06). https://doi.org/10.1109/SC.2006.54
- 32.Jorgensen WL (2006) QikProp. Schrödinger LLC, New YorkGoogle Scholar