Repurposing of US-FDA-approved Drugs as Negative Modulators of Ubiquitin Specific Protease-7 (USP7)

Authors

Seema Zadi, University of Karachi
Sumaira Javaid, University of Karachi
Atia-tul-Wahab, University of Karachi
Humaira Zafar, University of Karachi
Muhammad Awais, University of Karachi
Innokentiy Maslennikov, Chapman UniversityFollow
M. Iqbal Choudhary, University of Karachi

Document Type

Article

Publication Date

2-23-2024

Abstract

Ubiquitin-specific protease7 (USP7) regulates the stability of the p53 tumor suppressor protein and several other proteins critical for tumor cell survival. Aberrant expression of USP7 facilitates human malignancies by altering the activity of proto-oncogenes/proteins, and tumor suppressor genes. Therefore, USP7 is a validated anti-cancer drug target. In this study, a drug repurposing approach was used to identify new hits against the USP7 enzyme. It is one of the most strategic approaches to find new uses for drugs in a cost- and time-effective way. Nuclear Magnetic Resonance-based screening of 172 drugs identified 11 compounds that bind to the catalytic domain of USP7 with dissociation constant (Kd) values in the range of 0.6–1.49 mM. These 11 compounds could thermally destabilize the USP7 enzyme by decreasing its melting temperature up to 9 °C. Molecular docking and simulation studies provided structural insights into the ligand-protein complexes, suggesting that these compounds bind to the putative substrate binding pocket of USP7, and interact with its catalytically important residues. Among the identified 11 hits, compound 6 (oxybutynin), 7 (ketotifen), 10 (pantoprazole sodium), and 11 (escitalopram) also showed anti-cancer activity with an effect on the expression of proto-oncogenes and tumor-suppressor gene at mRNA level in HCT116 cells. The compounds identified in this study can serve as potential leads for further studies.

Comments

This article was originally published in Heliyon, volume 10, issue 5, in 2024. https://doi.org/10.1016/j.heliyon.2024.e26345

Recommended Citation

Zadi S, Javaid S, Atia-tul-Wahab, et al. Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7). Heliyon. 2024; 10(5):e26345. https://doi.org/10.1016/j.heliyon.2024.e26345

Copyright

Elsevier

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.