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

Joel Ricci-López, Abraham Vidal-Limon, Matías Zunñiga, Verónica A. Jimènez, Joel B. Alderete, Carlos A. Brizuela, Sergio Aguila

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

6 Citas (Scopus)

Resumen

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.

Idioma originalInglés
Número de artículoe0213028
PublicaciónPLoS ONE
Volumen14
N.º3
DOI
EstadoPublicada - 1 mar 2019

Áreas temáticas de ASJC Scopus

  • Bioquímica, genética y biología molecular (todo)
  • Agricultura y biología (todo)

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