Title

Molecular modeling simulation studies reveal new potential inhibitors against HPV E6 protein

Author

Joel Ricci-Lopez

Contributor

Abraham Marcelino Vidal Limón (Collaborator)

Matias Zuñiga (Collaborator)

Veronica Jimenez (Collaborator)

Joel B Alderete (Collaborator)

Carlos Alberto Brizuela Rodríguez (Collaborator)

Sergio A. Aguila (Collaborator)

Access level

Open Access

Alternative identifier

doi: https://doi.org/10.1371/journal.pone.0213028

Summary or description

High-risk strains of human papillomavirus (HPV) have been identified as the etiologic agent of some anogenital tract, head, and neck cancers. Although prophylactic HPV vaccines have been approved; it is still necessary a drug-based treatment against the infection and its oncogenic effects. The E6 oncoprotein is one of the most studied therapeutic targets of HPV, it has been identified as a key factor in cell immortalization and tumor progression in HPV-positive cells. E6 can promote the degradation of p53, a tumor suppressor protein, through the interaction with the cellular ubiquitin ligase E6AP. Therefore, preventing the formation of the E6-E6AP complex is one of the main strategies to inhibit the viability and proliferation of infected cells. Herein, we propose an in silico pipeline to identify small-molecule inhibitors of the E6-E6AP interaction. Virtual screening was carried out by predicting the ADME properties of the molecules and performing ensemble-based docking simulations to E6 protein followed by binding free energy estimation through MM/PB(GB)SA methods. Finally, the top-three compounds were selected, and their stability in the E6 docked complex and their effect in the inhibition of the E6-E6AP interaction was corroborated by molecular dynamics simulation. Therefore, this pipeline and the identified molecules represent a new starting point in the development of anti-HPV drugs. © 2019 Ricci-López et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publish date

2019

Publication type

Article

Publication version

Published Version

Format

application/pdf

Source

PLoS ONE, Vol.14, No.3, Pags. 1-22

Language

English

Citation suggestion

Ricci-López J, Vidal-Limon A, Zunñiga M, Jimènez VA, Alderete JB, Brizuela CA, et al. (2019) Molecular modeling simulation studies reveal new potential inhibitors against HPV E6 protein. PLoS ONE 14(3): e0213028. https://doi.org/10.1371/journal.pone.0213028

Source repository

Repositorio Institucional CICESE

Downloads

16

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