Targeting IDH1 (R132H)-Driven Oncometabolic Vulnerabilities: Structure-Guided Discovery of Phytochemical Inhibitor

Mutations in IDH1, particularly the recurrent R132H substitution, drive oncogenesis through neomorphic production of the oncometabolite D-2-hydroxyglutarate, creating a targetable metabolic vulnerability in malignancies such as low-grade glioma, acute myeloid leukemia, chondrosarcoma, and cholangiocarcinoma. Although small-molecule inhibitors targeting mutant IDH1 have demonstrated clinical benefit, challenges related to resistance, accessibility, and cost highlight the need for alternative scaffolds. In this study, a structure-guided in silico workflow integrating molecular docking, drug-likeness filtering, molecular dynamics simulations, and MM/GBSA binding free energy estimation was employed to identify phytochemical inhibitors of IDH1 R132H from the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT 2.0) database. Four phytochemicals, kuwanol D, secodine, munjistin, and (-)-8-oxocanadine, were prioritized and benchmarked against reference inhibitors ivosidenib and olutasidenib. All selected compounds demonstrated stable binding within the mutant-specific catalytic pocket, supported by conserved interactions with key residues. Docking scores ranged from −9.13 to −10.06 kcal/mol, compared to −7.68 and −7.47 kcal/mol for the reference inhibitors. Molecular dynamics simulations (500 ns) revealed stable protein–ligand complexes, with (-)-8-oxocanadine exhibiting tightly confined ligand RMSD (∼1.0–1.5 Å) and the most favourable MM/GBSA binding free energy (−66.6 ± 5.6 kcal/mol). These findings suggest that selected phytochemicals can engage the mutant IDH1 catalytic pocket with favourable binding characteristics. However, given the predictive nature of computational approaches, experimental validation is required to confirm their inhibitory potential. Among the identified candidates, (-)-8-oxocanadine emerges as a structurally distinct scaffold warranting further investigation as a potential modulator of IDH1-driven onco-metabolic pathways.