Targeting IDH-driven Oncometabolism in glioblastoma: a computational approach for the identification of potential inhibitors

Abstract

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. 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. 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. 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.