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Updated: Sep 11, 2026
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Targeting IDH-driven Oncometabolism in glioblastoma: a computational approach for the identification of potential
Nivedhitha Tamilazhagan1, Sivakumar Arumugam1
1School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
Background:
Glioblastoma (GBM) is a malignant brain tumor frequently driven by mutations in isocitrate dehydrogenase (IDH1 and IDH2) enzymes, which promote neomorphic synthesis of the oncometabolite 2-hydroxyglutarate (2-HG) and subsequent metabolic dysfunction. Although these mutations are associated with different clinical outcomes, therapeutic intervention remains challenging due to tumor heterogeneity, cellular plasticity, restricted blood-brain barrier permeability, drug efflux mechanisms, and effective DNA repair pathways. Therefore, this study aims to identify selective inhibitors of mutant IDH proteins by overcoming these challenges.
Methods:
10,309 compounds from ChemFaces and MedChemExpress libraries are used for large-scale virtual screening and multi-level ADMET filtering, uncovering 19 lead compounds with favourable drug-likeness. Further, molecular docking followed by 300 ns of molecular dynamics simulations, PCA analysis, and MM-PBSA calculations were performed to explore conformational dynamics.
Results:
Molecular docking revealed strong binding affinities of PubChem ID 91457 (I1Hit1) as -7.57 kcal/mol and PubChem ID 4946 (I1Hit2) as -6.82 kcal/mol against IDH1, and PubChem ID 71550939 (I2Hit1) as -11.23 kcal/mol and PubChem ID 4946 (I2Hit2) as -7.87 kcal/mol against IDH2, by outperforming the standard (-6.17 kcal/mol). Molecular dynamics simulations, PCA analysis, and MM-PBSA calculations confirmed complex stability and inhibitory potential. Notably, I1Hit1 and I2Hit1 exhibited enhanced binding free energies of -20.67 ± 2.32 kcal/mol against IDH1 and -28.78 ± 2.67 kcal/mol against IDH2 respectively, compared to the standard, as further supported by computational pharmacophore evaluation.
Conclusion:
Collectively, these findings highlight I1Hit1 and I2Hit1 as novel therapeutic compounds with efficient IDH-target inhibition to address epigenetic modification in GBM, and further experimental validation of these compounds is required to demonstrate potential inhibitors of IDH-driven metabolism in GBM.
