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

ABSTRACT: 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.

SUBMITTER: Ricci-Lopez J

PROVIDER: S-EPMC6420176 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Ricci-López Joel J Vidal-Limon Abraham A Zunñiga Matías M Jimènez Verónica A VA Alderete Joel B JB Brizuela Carlos A CA Aguila Sergio S

PloS one 20190315 3

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 degradat ...[more]

PMID: 30875378

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Project description:Persons living with human immunodeficiency virus (HIV) have a disproportionately higher burden of human papillomavirus infection (HPV)-related cancers. Causal factors include both behavioral and biological. While pharmaceutical and care support interventions help address biological risk of coinfection, as social conditions are common drivers of behaviors, structural interventions are key part of behavioral interventions. Our objective is to develop a joint HIV-HPV model to evaluate the contribution of each factor, to subsequently inform intervention analyses. While compartmental modeling is sufficient for faster spreading HPV, network modeling is suitable for slower spreading HIV. However, using network modeling for jointly modeling HIV and HPV can generate computational complexities given their vastly varying disease epidemiology and disease burden across sub-population groups. We applied a recently developed mixed agent-based compartmental (MAC) simulation technique, which simulates persons with at least one slower spreading disease and their immediate contacts as agents in a network, and all other persons including those with faster spreading diseases in a compartmental model, with an evolving contact network algorithm maintaining the dynamics between the two models. We simulated HIV and HPV in the U.S. among heterosexual female, heterosexual male, and men who have sex with men (men only and men and women) (MSM), sub-populations that mix but have varying HIV burden, and cervical cancer among women. We conducted numerical analyses to evaluate the contribution of behavioral and biological factors to risk of cervical cancer among women with HIV. The model outputs for HIV, HPV, and cervical cancer compared well with surveillance estimates. Model estimates for relative prevalence of HPV (1.67 times) and relative incidence of cervical cancer (3.6 times), among women with HIV compared to women without, were also similar to that reported in observational studies in the literature. The fraction attributed to biological factors ranged from 22-38% for increased HPV prevalence and 80% for increased cervical cancer incidence, the remaining attributed to behavioral. The attribution of both behavioral and biological factors to increased HPV prevalence and cervical cancer incidence suggest the need for behavioral, structural, and pharmaceutical interventions. Validity of model results related to both individual and joint disease metrics serves as proof-of-concept of the MAC simulation technique. Understanding the contribution of behavioral and biological factors of risk helps inform interventions. Future work can expand the model to simulate sexual and care behaviors as functions of social conditions to jointly evaluate behavioral, structural, and pharmaceutical interventions for HIV and cervical cancer prevention.

Dataset Information

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

Publications

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

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