In-Silico Investigation of GRP78 Inhibition in Glioblastoma: Implications for Therapeutic Targeting

Document Type : Regular Articles

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1 Physics Department, Faculty of Science, Sohag University, Sohag, 82524, Egypt

2 Biophysics Department, Faculty of Science, Cairo University, Giza, 12613, Egypt

Abstract

Glioblastoma (GBM) is an aggressive, fast-growing, and treatment-resistant tumor with high recurrence and poor prognosis. GRP78 is a molecular chaperone implicated in cancer cell survival, proliferation, and stress response, and overexpression has been shown to play a role in GBM development and drug resistance. In this work, we examine Zidovudine triphosphate (ZDV-TP) as a potential GRP78 inhibitor by computational approaches, including molecular docking, molecular dynamics (MD) simulations, and MMGBSA calculations. The results indicate that ZDV-TP securely binds to and energetically favors the ATP-binding site of GRP78, suggesting that it could disrupt its chaperone function. 100 ns MD simulations show that the GRP78-ZDV-TP complex is stable without significant conformational change, implying no destabilization of the protein structure. Such findings form a foundation that ZDV-TP is effective in inhibiting GRP78 and can abolish its role in GBM tumor formation and drug resistance. Further experimental proof should be tested for ZDV-TP to be an auspicious therapeutic target of GBM.

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