Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7)
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. Th...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-03-01
|
| Series: | Heliyon |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024023764 |
| _version_ | 1827316552836317184 |
|---|---|
| author | Seema Zadi Sumaira Javaid Atia-tul-Wahab Humaira Zafar Muhammad Awais Innokentiy Maslennikov M. Iqbal Choudhary |
| author_facet | Seema Zadi Sumaira Javaid Atia-tul-Wahab Humaira Zafar Muhammad Awais Innokentiy Maslennikov M. Iqbal Choudhary |
| author_sort | Seema Zadi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:29:17Z |
| format | Article |
| id | doaj.art-a3f986d778754196a171c92e4a18f2ae |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-24T23:16:28Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-a3f986d778754196a171c92e4a18f2ae2024-03-17T07:55:18ZengElsevierHeliyon2405-84402024-03-01105e26345Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7)Seema Zadi0Sumaira Javaid1 Atia-tul-Wahab2Humaira Zafar3Muhammad Awais4Innokentiy Maslennikov5M. Iqbal Choudhary6Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, 75270, PakistanDr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Corresponding author. International Center of Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, 75270, PakistanDr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, 75270, PakistanDr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, 75270, PakistanSchool of Pharmacy, Chapman University Irvine, CA, 92866, USADr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, 22252, Saudi Arabia; Corresponding author. International Center of Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.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.http://www.sciencedirect.com/science/article/pii/S2405844024023764Drug repurposingDeubiquitinaseUSP7Anti-cancer agentsSTD-NMRGene expression analysis |
| spellingShingle | Seema Zadi Sumaira Javaid Atia-tul-Wahab Humaira Zafar Muhammad Awais Innokentiy Maslennikov M. Iqbal Choudhary Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7) Heliyon Drug repurposing Deubiquitinase USP7 Anti-cancer agents STD-NMR Gene expression analysis |
| title | Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7) |
| title_full | Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7) |
| title_fullStr | Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7) |
| title_full_unstemmed | Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7) |
| title_short | Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7) |
| title_sort | repurposing of us fda approved drugs as negative modulators of ubiquitin specific protease 7 usp7 |
| topic | Drug repurposing Deubiquitinase USP7 Anti-cancer agents STD-NMR Gene expression analysis |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024023764 |
| work_keys_str_mv | AT seemazadi repurposingofusfdaapproveddrugsasnegativemodulatorsofubiquitinspecificprotease7usp7 AT sumairajavaid repurposingofusfdaapproveddrugsasnegativemodulatorsofubiquitinspecificprotease7usp7 AT atiatulwahab repurposingofusfdaapproveddrugsasnegativemodulatorsofubiquitinspecificprotease7usp7 AT humairazafar repurposingofusfdaapproveddrugsasnegativemodulatorsofubiquitinspecificprotease7usp7 AT muhammadawais repurposingofusfdaapproveddrugsasnegativemodulatorsofubiquitinspecificprotease7usp7 AT innokentiymaslennikov repurposingofusfdaapproveddrugsasnegativemodulatorsofubiquitinspecificprotease7usp7 AT miqbalchoudhary repurposingofusfdaapproveddrugsasnegativemodulatorsofubiquitinspecificprotease7usp7 |