Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Targeting BRF2 in Cancer with Repurposed Drugs Using in Silico Methods

Behnam Rashidieh
* ORCID logo ,
Maryam Molakarimi
,
Ammar Mohseni
,
Hein Truong
,
Sriganesh Srihari
,
Rachael C. Adams
,
Pascal H.G. Duijf
,
Murugan Kalimutho
ORCID logo ,
Kum Kum Khanna
* ORCID logo
Version 1 : Received: 30 December 2020 / Approved: 31 December 2020 / Online: 31 December 2020 (08:49:33 CET)
Version 2 : Received: 16 July 2021 / Approved: 16 July 2021 / Online: 16 July 2021 (11:40:34 CEST)

A peer-reviewed article of this Preprint also exists.

Rashidieh, B.; Molakarimi, M.; Mohseni, A.; Tria, S. M.; Truong, H.; Srihari, S.; Adams, R. C.; Jones, M.; Duijf, P. H. G.; Kalimutho, M.; et al. Targeting BRF2 in Cancer Using Repurposed Drugs. Cancers, 2021, 13, 3778. https://doi.org/10.3390/cancers13153778. Rashidieh, B.; Molakarimi, M.; Mohseni, A.; Tria, S. M.; Truong, H.; Srihari, S.; Adams, R. C.; Jones, M.; Duijf, P. H. G.; Kalimutho, M.; et al. Targeting BRF2 in Cancer Using Repurposed Drugs. Cancers, 2021, 13, 3778. https://doi.org/10.3390/cancers13153778.

Abstract

Overexpression of BRF2, the essential subunit of RNA polymerase III, is required for the development of a variety of cancers, including lung squamous cell carcinoma and breast cancer. BRF2 also acts as a central redox-sensing transcription factor (TF) and is involved in the regulation of oxidative stress (OS) pathway where its amplification enables cancer cells to evade OS-induced apoptosis. Here, we experimentally confirmed a link between BRF2 and DNA damage response (DDR) signaling. Focusing on its DNA binding capacity, we targeted BRF2-TATA binding Protein (TBP)-DNA complex interaction to functionally inhibit this transcription factor (TF). We found that BRF2 binding to TBP changes the conformation of this protein and therefore characterized these events in detail. Virtual screening allowed selection of the optimal drug based on binding energy, and intermolecular, internal, and torsional energy parameters. Molecular dynamics simulation confirmed the docking results and all simulations were validated by root‐mean‐square deviation (RMSD). According to the simulation, the chosen drug was efficacious in targeting BRF2 which therefore requires further experimental validation to investigate the effect of this drug on BRF2 functions and its downstream pathways.

Keywords

BRF2; cancer; molecular dynamics simulation; drug repurposing; drug discovery

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF Download Supplementary

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0
Get PDF Supplementary Files Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.