Modelling of Hepatitis E virus RNA-dependent RNA polymerase genotype 3 from a chronic patient and in silico interaction analysis by molecular docking with Ribavirin

Abstract

Hepatitis E Virus (HEV) infection is an emergent zoonotic disease, where chronic hepatitis E associated to solid organ transplant (SOT) recipients, related to genotype 3, is the clinical manifestation of major concern. In this setting, ribavirin (RBV) treatment is the only available therapy, though drug-resistant variants could emerge leading to a therapeutic failure. Crystallographic structures have not been reported for most of the HEV proteins, including the RNA-polymerase (RdRp). Therefore, the mechanism of action of RBV against HEV and the molecular interactions between this drug and RdRp are largely unknown. In this work, we aimed to model in silico the 3 D structure of a novel HEV3 RdRp (HEV_C1_Uy) from a chronically HEV infected-SOT recipient treated with RBV and to perform a molecular docking simulation between RBV triphosphate (RBVT), 7-methyl-guanosine-5'-triphosphate and the modelled protein. The models were generated using I-TASSER server and validated with multiple bioinformatics tools. The docking analysis were carried out with AutoDock Vina and LeDock software. We obtained a suitable model for HEV_C1_Uy (C-Score=-1.33, RMSD = 10.4 ± 4.6 Å). RBVT displayed a binding affinity of −7.6 ± 0.2 Kcal/mol by molecular docking, mediated by 6 hydrogen-bonds (Q195-O14, S198-O11, E257-O13, S260-O2, O3, S311-O11) between the finger’s-palm-domains and a free binding energy of 31.26 ± 16.81 kcal/mol by molecular dynamics simulations. We identified the possible HEV RdRp interacting region for incoming nucleotides or analogs and provide novel insights that will contribute to better understand the molecular interactions of RBV and the enzyme and the mechanism of action of this antiviral drug.

Communicated by Ramaswamy H. Sarma.

Keywords:

• Hepatitis E virus
• RNA polymerase
• ribavirin
• molecular docking
• interaction
• structure

Disclosure statement

The authors declare that there are no conflicts of interest.

Author contributions

Conceptualization, C.Q-G and F.C.; methodology, F.C., S.R-M., Y.P., R.P., D.R.H; software, F.C., S.R-M. D.R.H., G.G.; validation, F.C. and S.R-M.; formal analysis, F.C., S.R-M., C.Q-G. D.R.H., G.G and S.M.,; investigation, F.C.; S.M.; resources, S.M.; data curation, Y.P., R.P.; writing—original draft preparation, F.C.; writing—review and editing, C.Q-G., S.R-M., Y.P., R.P., D.R.H., G.G. and S.M.; visualization, F.C., S.M.; supervision, C.Q-G. and S.M.; project administration, S.M, J.A.; funding acquisition, S.M. and J.A. All authors have read and agreed to the published version of the manuscript.

Ethical approval

The study was approved by the Ethics Committee from the Hospital Central de las Fuerzas Armadas.

Ethical approval number 07/CE/19.

Informed consent

The patient gave written informed consent

Additional information

Funding

This work was supported by the Comisión Sectorial de Investigación Científica-UdelaR, under grant [CSIC I + D 2018 #245]. F.C. PhD fellowship by Comisión Académica de Posgrado-UdelaR. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.