Conformational diversity and protein–protein interfaces in drug repurposing in Ras signaling pathway
Abstract We focus on drug repurposing in the Ras signaling pathway, considering structural similarities of protein–protein interfaces. The interfaces formed by physically interacting proteins are found from PDB if available and via PRISM (PRotein Interaction by Structural Matching) otherwise. The st...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-50913-8 |
| _version_ | 1797355788648316928 |
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| author | Ahenk Zeynep Sayin Zeynep Abali Simge Senyuz Fatma Cankara Attila Gursoy Ozlem Keskin |
| author_facet | Ahenk Zeynep Sayin Zeynep Abali Simge Senyuz Fatma Cankara Attila Gursoy Ozlem Keskin |
| author_sort | Ahenk Zeynep Sayin |
| collection | DOAJ |
| description | Abstract We focus on drug repurposing in the Ras signaling pathway, considering structural similarities of protein–protein interfaces. The interfaces formed by physically interacting proteins are found from PDB if available and via PRISM (PRotein Interaction by Structural Matching) otherwise. The structural coverage of these interactions has been increased from 21 to 92% using PRISM. Multiple conformations of each protein are used to include protein dynamics and diversity. Next, we find FDA-approved drugs bound to structurally similar protein–protein interfaces. The results suggest that HIV protease inhibitors tipranavir, indinavir, and saquinavir may bind to EGFR and ERBB3/HER3 interface. Tipranavir and indinavir may also bind to EGFR and ERBB2/HER2 interface. Additionally, a drug used in Alzheimer's disease can bind to RAF1 and BRAF interface. Hence, we propose a methodology to find drugs to be potentially used for cancer using a dataset of structurally similar protein–protein interface clusters rather than pockets in a systematic way. |
| first_indexed | 2024-03-08T14:16:09Z |
| format | Article |
| id | doaj.art-70300b18ef7b452c89a30866895f8214 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-08T14:16:09Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-70300b18ef7b452c89a30866895f82142024-01-14T12:23:38ZengNature PortfolioScientific Reports2045-23222024-01-0114111710.1038/s41598-023-50913-8Conformational diversity and protein–protein interfaces in drug repurposing in Ras signaling pathwayAhenk Zeynep Sayin0Zeynep Abali1Simge Senyuz2Fatma Cankara3Attila Gursoy4Ozlem Keskin5Department of Chemical and Biological Engineering, College of Engineering, Koc UniversityGraduate School of Science and Engineering, Computational Sciences and Engineering, Koc UniversityGraduate School of Science and Engineering, Computational Sciences and Engineering, Koc UniversityGraduate School of Science and Engineering, Computational Sciences and Engineering, Koc UniversityDepartment of Computer Engineering, Koc UniversityDepartment of Chemical and Biological Engineering, College of Engineering, Koc UniversityAbstract We focus on drug repurposing in the Ras signaling pathway, considering structural similarities of protein–protein interfaces. The interfaces formed by physically interacting proteins are found from PDB if available and via PRISM (PRotein Interaction by Structural Matching) otherwise. The structural coverage of these interactions has been increased from 21 to 92% using PRISM. Multiple conformations of each protein are used to include protein dynamics and diversity. Next, we find FDA-approved drugs bound to structurally similar protein–protein interfaces. The results suggest that HIV protease inhibitors tipranavir, indinavir, and saquinavir may bind to EGFR and ERBB3/HER3 interface. Tipranavir and indinavir may also bind to EGFR and ERBB2/HER2 interface. Additionally, a drug used in Alzheimer's disease can bind to RAF1 and BRAF interface. Hence, we propose a methodology to find drugs to be potentially used for cancer using a dataset of structurally similar protein–protein interface clusters rather than pockets in a systematic way.https://doi.org/10.1038/s41598-023-50913-8 |
| spellingShingle | Ahenk Zeynep Sayin Zeynep Abali Simge Senyuz Fatma Cankara Attila Gursoy Ozlem Keskin Conformational diversity and protein–protein interfaces in drug repurposing in Ras signaling pathway Scientific Reports |
| title | Conformational diversity and protein–protein interfaces in drug repurposing in Ras signaling pathway |
| title_full | Conformational diversity and protein–protein interfaces in drug repurposing in Ras signaling pathway |
| title_fullStr | Conformational diversity and protein–protein interfaces in drug repurposing in Ras signaling pathway |
| title_full_unstemmed | Conformational diversity and protein–protein interfaces in drug repurposing in Ras signaling pathway |
| title_short | Conformational diversity and protein–protein interfaces in drug repurposing in Ras signaling pathway |
| title_sort | conformational diversity and protein protein interfaces in drug repurposing in ras signaling pathway |
| url | https://doi.org/10.1038/s41598-023-50913-8 |
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