Comprehensive quantum chemical analysis, vibrational spectroscopy, molecular docking, ADMET, and in vitro validation studies of hydroxychloroquine-MRGPRX2 complex in IDH-wildtype glioblastoma
Abstract
Glioblastoma is an aggressive astrocytic neoplasm characterized by significant intratumoral heterogeneity and resistance to standard therapies. Despite advances such as the Stupp protocol, the prognosis remains poor, with a median survival of 12-15 months. Mast cells in the tumor microenvironment (TME) release pro-inflammatory mediators, promoting tumor progression and therapeutic resistance. The Mas-related G protein-coupled receptor X2 (MRGPRX2), expressed on mast cells, is implicated in neuroinflammatory regulation. This study evaluates hydroxychloroquine (HCQ), a 4-aminoquinoline derivative, as a potential MRGPRX2 inhibitor using a comprehensive multidisciplinary approach. Density Functional Theory (DFT) at the B3LYP/6-31 + G(d,p) level was employed to analyze the structural and electronic properties of HCQ, validated by FTIR and Raman spectroscopy. To ensure statistical robustness and address receptor specificity, 100 independent blind docking simulations were performed using the high-resolution MRGPRX2 structure (PDB ID: 7S8L). The docking protocol was rigorously validated through a cross-docking study using the 7S8N reference ligand, yielding a high spatial consensus with an RMSD of 3.06 Å. The results revealed that HCQ possesses a superior binding affinity of -7.0 kcal/mol, while comparative docking with the standard therapeutic Temozolomide (TMZ) yielded a lower affinity of -5.6 kcal/mol. Detailed residue-level analysis highlighted a distinct binding fingerprint for…
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