Identification and Characterization of Potential Inhibitors Against <i>Drosophila</i> Brain Tumor Protein BRAT Using Computational Approaches: A Preliminary Step towards Targeting Human Gliomas

Abstract Drosophila brain tumor (BRAT) protein plays key roles in neural stem cell regulation and brain tumor formation in fruitflies. While its direct involvement in human glioma pathogenesis is not fully established, BRAT is a potential therapeutic target because it affects oncological pathways which may be conserved across species. The study explores natural products and drug‐like compounds as inhibitors of the BRAT protein. The 3D crystal structure of BRAT (PDB‐ID: 4ZLR) was refined to address missing residues, ensuring structural integrity. After identification of druggable pockets, virtual screening of 150,000 compounds from natural product and drug libraries was performed. Based upon binding affinities and other interaction parameter scores, ZINC000003831419 and ZINC000067913658 were selected for further analysis. Simulations confirmed the stability of these protein‐ligand complexes, with root‐mean‐square deviation (RMSD) and root‐mean‐square fluctuation (RMSF) values indicating minimal structural fluctuations. Further, significant collective motions induced by ligand binding, and cross‐correlation analysis demonstrated cooperative residue behavior, indicating high stability. The binding free energy calculations validated the strong affinities of the two compounds, highlighting the importance of hydrogen bonds and hydrophobic interactions in ligand binding. The findings establish ZINC000003831419 and ZINC000067913658 as promising candidates for glioblastoma therapy, warranting further experimental validation.