Virtual drug screening for p65/rela subunit of nf-κb: Promising repurposable drugs in the treatment of stress-based diseases

Abstract

Background and Aims: Although NF-kappa B is composed of five subunits, RelA receives much more attention due to fact that its expression level is regulated under various stress conditions, such as exposure to radiation, reactive oxygen species (ROS), hypoxia, pathogens, and inflammatory cytokines, as well as regulating many inflammatory, proliferation, and apoptosis genes. To date, many pieces of evidence have demonstrated that RelA plays a significant role in in the prognosis of various proliferative and inflammatory diseases. Therefore, the design of novel inhibitors and the discovery of repurposable drugs are considered promising approaches in the treatment of RelA-based diseases.Methods: A drug library including a total of 12,111 ligands has been screened for the RelA subunit of NF-kappa B. The sufficiency of the study's strategy has been revealed by analysis of commercially available inhibitors and re-docking applications.Results: Findings demonstrate that ZINC000096928979 (Deleobuvir), ZINC000012503187 (Conivaptan), and ZINC000003974230 ligands have the highest binding affinity to RelA. Furthermore, many ligands with structural similarities to Valstar, Ergotamine drugs and Benzo[a]pyrene-7,8-Diol metabolite have been discovered.Conclusion: While the ligands with the highest binding affinities could be repurposed in the treatment of RelA-based diseases, the structures of the ligands exhibiting similarity with Valstar, Ergotamine, and Benzo[a]pyrene-7, 8-D may be used as a scaffold in structure-based drug design studies. The stability of the interactions between the ligands and the receptor should be analyzed with further Molecular Dynamics Simulations (MD) studies and the possible ligands should be investigated by both in vitro and in vivo applications.