In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma
Abstract Glioblastoma multiforme (GBM) is one of the most malignant tumors in central nervous system (CNS) tumors. The glucose-regulated protein 78 (GRP78) and CRIPTO (Cripto-1), a protein that belongs to the EGF-CFC (epidermal growth factor cripto-1 FRL-1 cryptic) family, are overexpressed in GBM....
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Nature Portfolio
2025-05-01
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| author | Mahmoud E. Rashwan Mahrous R. Ahmed Abdo A. Elfiky |
| author_facet | Mahmoud E. Rashwan Mahrous R. Ahmed Abdo A. Elfiky |
| author_sort | Mahmoud E. Rashwan |
| collection | DOAJ |
| description | Abstract Glioblastoma multiforme (GBM) is one of the most malignant tumors in central nervous system (CNS) tumors. The glucose-regulated protein 78 (GRP78) and CRIPTO (Cripto-1), a protein that belongs to the EGF-CFC (epidermal growth factor cripto-1 FRL-1 cryptic) family, are overexpressed in GBM. A complex between GRP78 SBDβ (substrate binding domain beta) and CRIPTO CFC domain was reported in previous studies. This complex activates MAPK/AKT signaling, Src/PI3K/AKT, and Smad2/3 pathways which is a reason for tumor proliferation. In this work, we study how the two proteins form the complex figuring out binding sites between GRP78 and CRIPTO utilizing computational biophysics and bioinformatics tools, such as protein–protein docking, molecular dynamics simulation and MMGBSA calculations. Haddock web server results of 4 regions from the CFC domain (region1 (− 70.4), region2 (− 78.7), region3 (− 74.2), region4 (− 86.8)) with selected residues of the SBDβ are then simulated for 100 ns MDS then MMGBSA were calculated for the four complexes. The results reveal the stability of the complexes with binding free energy (complex1 (− 15.07 kcal/mol), complex2 (− 59.78 kcal/mol), complex3 (− 81.92 kcal/mol), complex4 (− 126.26 kcal/mol). All these findings ensure that GRP78 SBDβ associates with the CRIPTO CFC domain, and the binding sites suggested make stable interactions between the proteins. |
| format | Article |
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| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-756443fc9a0e49c5a0bb0bb19979cb702025-08-20T03:10:17ZengNature PortfolioScientific Reports2045-23222025-05-0115111510.1038/s41598-025-00125-zIn silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastomaMahmoud E. Rashwan0Mahrous R. Ahmed1Abdo A. Elfiky2Physics Department, Faculty of Science, Sohag UniversityPhysics Department, Faculty of Science, Sohag UniversityBiophysics Department, Faculty of Science, Cairo UniversityAbstract Glioblastoma multiforme (GBM) is one of the most malignant tumors in central nervous system (CNS) tumors. The glucose-regulated protein 78 (GRP78) and CRIPTO (Cripto-1), a protein that belongs to the EGF-CFC (epidermal growth factor cripto-1 FRL-1 cryptic) family, are overexpressed in GBM. A complex between GRP78 SBDβ (substrate binding domain beta) and CRIPTO CFC domain was reported in previous studies. This complex activates MAPK/AKT signaling, Src/PI3K/AKT, and Smad2/3 pathways which is a reason for tumor proliferation. In this work, we study how the two proteins form the complex figuring out binding sites between GRP78 and CRIPTO utilizing computational biophysics and bioinformatics tools, such as protein–protein docking, molecular dynamics simulation and MMGBSA calculations. Haddock web server results of 4 regions from the CFC domain (region1 (− 70.4), region2 (− 78.7), region3 (− 74.2), region4 (− 86.8)) with selected residues of the SBDβ are then simulated for 100 ns MDS then MMGBSA were calculated for the four complexes. The results reveal the stability of the complexes with binding free energy (complex1 (− 15.07 kcal/mol), complex2 (− 59.78 kcal/mol), complex3 (− 81.92 kcal/mol), complex4 (− 126.26 kcal/mol). All these findings ensure that GRP78 SBDβ associates with the CRIPTO CFC domain, and the binding sites suggested make stable interactions between the proteins.https://doi.org/10.1038/s41598-025-00125-zGRP78CriptoGlioblastoma multiformeComputational biophysicsProtein–protein docking, molecular dynamics simulation |
| spellingShingle | Mahmoud E. Rashwan Mahrous R. Ahmed Abdo A. Elfiky In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma Scientific Reports GRP78 Cripto Glioblastoma multiforme Computational biophysics Protein–protein docking, molecular dynamics simulation |
| title | In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma |
| title_full | In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma |
| title_fullStr | In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma |
| title_full_unstemmed | In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma |
| title_short | In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma |
| title_sort | in silico prediction of grp78 cripto binding sites to improve therapeutic targeting in glioblastoma |
| topic | GRP78 Cripto Glioblastoma multiforme Computational biophysics Protein–protein docking, molecular dynamics simulation |
| url | https://doi.org/10.1038/s41598-025-00125-z |
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