Targeting BRF2: insights from in silico screening and molecular dynamic simulations

Abstract

The Transcription factor II B (TFIIB)‑related factor 2 (BRF2) containing TFIIIB complex recruits RNA polymerase III multi-subunit complex to selective gene promoters that altogether are responsible for synthesizing a variety of small non-coding RNAs, including a special type of selenocysteine tRNA (tRNASec), micro-RNA (miRNA), and other regulatory RNAs. BRF2 has been identified as a potential oncogene that promotes cancer cell survival under oxidative stress through its genetic activation. The structure of the BRF2 protein was modeled using the Robetta server, refined, and validated using the Ramachandran plot. A virtual approach utilizing molecular docking was used to screen a natural compound library to determine potential compounds that can interact with the molecular pin motif of the BRF2 protein using Maestro (Schrodinger). Subsequent molecular dynamics simulation studies of the top four ligands that exhibited low glide scores were performed using GROMACS. The findings derived from the simulations, in conjunction with the exploration of hydrogen bonding patterns, evaluation of the free energy landscape, and thorough analysis of residue decomposition, collectively converged to emphasize the robust interaction characteristics exhibited by Ligand 366 (Deacetyl lanatoside C) and ligand 336 (Neogitogenin)—with the BRF2 protein. These natural compounds may be potential inhibitors of BRF2, which could modulate the regulation of selenoprotein synthesis in cancer cells. Targeting BRF2 using these promising compounds may offer a new therapeutic approach to sensitize cancer cells to ferroptosis and apoptosis.

Communicated by Ramaswamy H. Sarma

Keywords:

• BRF2
• selenoprotein
• ferroptosis
• deacetyl lanatoside C
• neogitogenin

Acknowledgments

The authors sincerely thank the Bioinformatics Resources and Applications Facility (BRAF), C-DAC, Pune, India, for generously providing permission to utilize their computational facilities. We thank Dr. Ramakrishnan Muthuswamy, Nanjing Forestry University, China, for the help rendered in creating the Biorender image. We thank Dr. Walter Mitchell, Discovery Life Sciences, Malden, for his help with language editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Maestro v13.5 (Schrodinger, LLC New York, NY, USA) is sponsored by SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India. Anuranjan Singh Rathore is supported by a Teaching Assistantship from SASTRA Deemed to be University. Dr. Kalimuthu Kalishwaralal was awarded the ‘MK Bhan Young Researcher Fellowship Program (YRFP) for 2020–2021’ (Ref: No, HRD-12/4/2020-AFS-DBT).