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-κB 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-κB. 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.

Keywords

• RelA (p65)
• NF-κB
• Virtual Drug Screening
• Molecular Docking
• Drug Repurpossing

References

1. Ali, F., Raufi, M. A., Washington, B., & Ghali, J. K. (2007). Conivap-tan: A dual receptor vasopressin V1a/V2 antagonist. Cardiovascu-larDrug Reviews, 25(3), 261-279. https://doi.Org/10.1111/j.1527— 3466.2007.00019.x google scholar
2. Balta, A. (1998). Activation of nuclear factor NF-kB in inflamma-tory bowel disease. Hellenic Journal of Gastroenterology, 11(2), 106-107. https://doi.org/10.1038/cr.2009.137 google scholar
3. Bell, E. W., & Zhang, Y. (2019). DockRMSD: an open-source tool for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism. Journal of Cheminformatics, 11(1), 40-49. https://doi.org/10.1186/s13321-019-0362-7 google scholar
4. Bernal-Mizrachi, L., Lovly, C. M., & Ratner, L. (2006). The role of NF-kB-1 and NF-kB-2-mediated resistance to apoptosis in lymphomas. Proceedings of the National Academy of Sci-ences of the United States of America, 103(24), 9220-9225. https://doi.org/10.1073/pnas.0507809103 google scholar
5. Bijli, K. M., Fazal, F., & Rahman, A. (2012). Regulation of Rela/p65 and endothelial cell inflammation by proline-rich tyrosine kinase 2. American Journal of Respiratory Cell and Molecular Biology, 47(5), 660-668. https://doi.org/10.1165/rcmb.2012-0047OC google scholar
6. Choi, S. H., Kim, M. Y., Yoon, Y. S., Koh, D. I., Kim, M. K., Cho, S. Y., ... Hur, M. W. (2019). Hypoxia-induced RelA/p65 derepresses SLC16A3 (MCT4) by downregulating ZBTB7A. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1862(8), 771-785. https://doi.org/10.1016/j.bbagrm.2019.06.004 google scholar
7. Chuang, T. Der, Rehan, A., & Khorram, O. (2020). Tranilast induces MiR-200c expression through blockade of RelA/p65 activity in leiomyoma smooth muscle cells. Fertility and Sterility, 113(6), 1308-1318. https://doi.org/10.1016/j.fertnstert.2019.12.002 google scholar
8. Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 1-13. https://doi.org/10.1038/srep42717 google scholar

9. Dallakyan, S., & Olson, A. (2015). Small-Molecule Library Screening by Docking with PyRx. In J. E. Hempel, C. H. Williams, & C. C. Hong (Eds.), i (pp. 243-250). Clifton, U.S.A.: New Jersey. google scholar
10. Darwish, M. A., Abo-Youssef, A. M., Messiha, B. A. S., Abo-Saif, A. A., & Abdel-Bakky, M. S. (2021). Resvera-trol inhibits macrophage infiltration of pancreatic islets in streptozotocin-induced type 1 diabetic mice via attenuation of the CXCL16/NF-k p65 signaling pathway. Life Sciences, 272, 1-9. https://doi.org/10.1016/j.lfs.2021.119250 google scholar
11. Dorrington, M. G., & Fraser, I. D. C. (2019). NF-kB signaling in macrophages: Dynamics, crosstalk, and signal integration. Frontiers in Immunology, 10, 1-12. https://doi.org/10.3389/fimmu.2019.00705 google scholar
12. Ghosh, G., Wang, V. Y. F., Huang, D. Bin, & Fusco, A. (2012). NF-kB regulation: Lessons from structures. Immuno-logical Reviews, 246(1), 36-58. https://doi.org/10.1111/j.1600-065X.2012.01097.x google scholar
13. Giridharan, S., & Srinivasan, M. (2018). Mechanisms of NF-kB p65 and strategies for therapeutic manipulation. Journal of Inflamma-tion Research, 11, 407-419. https://doi.org/10.2147/JIR.S140188 google scholar
14. Kaltschmidt, C., Greiner, J. F. W., & Kaltschmidt, B. (2021). The transcription factor nf-kb in stem cells and development. Cells, 10(8), 1-17. https://doi.org/10.3390/cells10082042 google scholar
15. Kim, K. M., Zhang, Y., Kim, B. Y., Jeong, S. J., Lee, S. A., Kim, G. Do., ... Jung, M. (2004). The p65 subunit of nuclear factor- k B is a molecular target for radiation sensitization of human squamous carcinoma cells. Molecular Cancer Therapeutics, 3(6), 693-698. https://doi.org/10.1158/1535-7163.693.3.6 google scholar
16. Larrey, D., Lohse, A. W., Trepo, C., Bronowicki, J. P., Arasteh, K., Bourliere, M., ... Kukolj, G. (2013). Antiviral effect, safety, and pharmacokinetics of five-day oral administration of deleobu-vir (BI 207127), an investigational hepatitis C virus RNA polymerase inhibitor, in patients with chronic hepatitis C. Antimicrobial Agents and Chemotherapy, 57(10), 4727-4735. https://doi.org/10.1128/AAC.00565-13 google scholar
17. Liu, T., Zhang, L., Joo, D.,& Sun, S. C. (2017). NF-kB signaling in inflammation. Signal Transduction and Targeted Therapy, 2, 1-9. https://doi.org/10.1038/sigtrans.2017.23 google scholar
18. Makarov, S. S. (2001). NF-kB in rheumatoid arthritis: A pivotal regu-lator of inflammation, hyperplasia, and tissue destruction. Arthritis Research, 3(4), 200-206. https://doi.org/10.1186/ar300 google scholar
19. Morgan, M. J., & Liu, Z. G. (2010). Reactive oxygen species in TNFa-induced signaling and cell death. Molecules and Cells, 30(1), 1-12. https://doi.org/10.1007/s10059-010-0105-0 google scholar
20. Perkins, N. D., & Gilmore, T. D. (2006). Good cop, bad cop: The different faces of NF-kB. Cell Death and Differentiation, 13(5), 759-772. https://doi.org/10.1038/sj.cdd.4401838 google scholar
21. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Green-blatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera - A visualization system for exploratory research and analy-sis. Journal of Computational Chemistry, 25(13), 1605-1612. https://doi.org/10.1002/jcc.20084 google scholar
22. Rahman, M. M., & McFadden, G. (2011). Modulation of NF-kB signalling by microbial pathogens. Nature Reviews Microbiology, 9(4), 291-306. https://doi.org/10.1038/nrmicro2539 google scholar
23. Ronin, E., Di Ricco, M. L., Vallion, R., Divoux, J., Kwon, H. K., Gregoire, S., . . . Salomon, B. L. (2019). The nf-kb rela transcription factor is critical for regulatory t cell activation and stability. Frontiers in Immunology, 10, 1-15. https://doi.org/10.3389/fimmu.2019.02487 google scholar
24. Sander, T. (2022, October 28). Molecular Properties Prediction - Osiris Property Explorer. (n.d.). Retrieved from https://www.organic-chemistry.org/prog/peo/ google scholar
25. Sun, S. C. (2011). Non-canonical NF-kB signaling pathway. Cell Re-search, 21(1), 71-85. https://doi.org/10.1038/cr.2010.177 google scholar
26. Trott, O., & Olson, A. J. (2011). AutoDock Vina: improv- google scholar
27. ing the speed and accuracy of docking with a new scoring function, efficient optimization and multithread-ing. Journal of Computational Chemistry, 17(3), 295-304. https://doi.org/10.1038/gt.2009.148.Progress google scholar
28. Wan, F., & Lenardo, M. J. (2010). The nuclear signaling of NF-kB: Current knowledge, new insights, and future perspectives. Cell Research, 20(1), 24-33. https://doi.org/10.1038/cr.2009.137 google scholar
29. Zarnegar, B., Yamazaki, S., He, J. Q., & Cheng, G. (2008). Con-trol of canonical NF-kB activation through the NIK-IKK com-plex pathway. Proceedings of the National Academy of Sci-ences of the United States of America, 105(9), 3503-3508. https://doi.org/10.1073/pnas.0707959105 google scholar
30. Zeltser, D., Rosansky, S., Van Rensburg, H., Verbalis, J. G., & Smith, N. (2007). Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hy-ponatremia. American Journal of Nephrology, 27(5), 447-457. https://doi.org/10.1159/000106456 google scholar
31. Zhang, H. N., Li, L., Gao, P., Chen, H. Z., Zhang, R., Wei, Y. S., . . . Liang, C. C. (2010). Involvement of the p65/RelA subunit of NF-kB in TNF-a-induced SIRTI expression in vascular smooth muscle cells. Biochemical and Biophysical Research Communications, 397(3), 569-575. https://doi.org/10.1016/j.bbrc.2010.05.160 google scholar
32. Zhang, T., Ma, C., Zhang, Z., Zhang, H., & Hu, H. (2021). NF-kB signaling in inflammation and cancer. MedComm, 2(4), 618-653. https://doi.org/10.1002/mco2.104 google scholar
33. Zhou, Y., Cui, C., Ma, X., Luo, W., Zheng, S. G., & Qiu, W. (2020). Nuclear Factor kB (NF- k B)-Mediated In-flammation in Multiple Sclerosis. Frontiers in Immunol-ogy, 11(March), 1-12. https://doi.org/10.3389/fimmu.2020.00391 ryearAuthor12007]aut google scholar