In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma

Mahmoud E Rashwan; Mahrous R Ahmed; Abdo A Elfiky

doi:10.1038/s41598-025-00125-z

In silico prediction of GRP78-CRIPTO binding sites to improve therapeutic targeting in glioblastoma

Sci Rep. 2025 May 13;15(1):16660. doi: 10.1038/s41598-025-00125-z.

Authors

Mahmoud E Rashwan¹, Mahrous R Ahmed², Abdo A Elfiky³

Affiliations

¹ Physics Department, Faculty of Science, Sohag University, Sohag, 82524, Egypt. mahmoud.ezz@science.sohag.edu.eg.
² Physics Department, Faculty of Science, Sohag University, Sohag, 82524, Egypt.
³ Biophysics Department, Faculty of Science, Cairo University, Giza, 12613, Egypt.

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.

Keywords: Computational biophysics; Cripto; GRP78; Glioblastoma multiforme; Protein–protein docking, molecular dynamics simulation.

MeSH terms

Binding Sites
Computational Biology
Endoplasmic Reticulum Chaperone BiP
GPI-Linked Proteins* / chemistry
GPI-Linked Proteins* / metabolism
Glioblastoma* / drug therapy
Glioblastoma* / metabolism
Heat-Shock Proteins* / chemistry
Heat-Shock Proteins* / metabolism
Humans
Intercellular Signaling Peptides and Proteins* / chemistry
Intercellular Signaling Peptides and Proteins* / metabolism
Molecular Docking Simulation
Molecular Dynamics Simulation
Neoplasm Proteins* / chemistry
Neoplasm Proteins* / metabolism
Protein Binding

Substances

Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
TDGF1 protein, human
Heat-Shock Proteins
Neoplasm Proteins
GPI-Linked Proteins
Intercellular Signaling Peptides and Proteins