De novo designed EBAI as a potential inhibitor of the viral protein BHRF1. Research in silico

Abstract

Epstein-Barr virus is a DNA-containing virus that, according to current data, is associated with approximately 1% of all cancers in the world. This viral effect on the human body is associated with its pronounced antiapoptotic activity. An important role in this process is played by the protein BHRF1, which is a structural and functional homologue of antiapoptotic proteins of the BCL-2 family. In this study, we investigate the selective low molecular weight inhibitor of the above viral protein – EBAI (Epstein-Barr virus Antiapoptotic Inhibitor), which we designed using in silico methods. We conducted two parallel simulation experiments where EBAI was intentionally destabilized to demonstrate its high-affinity recognition potential of the BHRF1 pocket, which binds BH3.Thus, although the potential inhibitor was in close proximity to the site of interaction, it contacted it only through orientation interactions (hydrogen and Coulomb interactions). Despite this complication of the standard ligand-receptor complex simulation procedure, we demonstrated in two parallel computational experiments the high affinity of EBAI for the BH3-binding pocket of BHRF1. In both cases, in the first nanoseconds of modeling, our inhibitor underwent the necessary conformational rearrangements and formed all the required interactions for effective complexation. Thus, further in vitro studies are logical and necessary step to fully evaluate the potential of EBAI as an inhibitor of the antiapoptotic protein BHRF1 of Epstein-Barr virus.

Communicated by Ramaswamy H. Sarma

Keywords:

• Epstein-Barr virus
• apoptosis
• GROMACS
• molecular modeling
• drug development

Disclosure statement

The authors declare that there is no conflict of interests.

Authors' contributions

Andrii A. Zaremba designed the model, performed the experiments and analysed the data. Polina Y. Zaremba wrote the manuscript with input from all authors. Maxim O. Platonov supervised the project.

Availability of data and material

The authors confirm that the data supporting the findings of this study are available within the article.

Code availability

Software application.

Additional information

Funding

The authors declare that this study did not have а financial support.