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

Joel Ricci-Lopez (2019)

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.

Artículo

ligand, luteolin, protein E6, protein inhibitor, ubiquitin protein ligase, ubiquitin protein ligase E6AP, unclassified drug, antivirus agent, DNA binding protein, E6 protein, Human papillomavirus type 18, oncoprotein, protein binding, protein p53, TP CIENCIAS AGROPECUARIAS Y BIOTECNOLOGÍA CIENCIAS AGROPECUARIAS Y BIOTECNOLOGÍA