Aug 2026· Frontiers in Bioinformatics· Vol 6· 0 citations· 76 references
Medicine
TL;DR
I1Hit1 and I2Hit1 are highlighted 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.
Abstract
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.
These findings establish mitochondrial malic enzymes, particularly ME2/ME3, as tractable metabolic targets for cancer therapy, and provide a strong foundation for rational optimization of potency and isoform selectivity.
Ben A. Krinkel, Y. Yosaatmadja, M. Slayton et al.· Clinical Cancer Research· 0 citations
Dual blockade of mutant IDH and glutaminolysis represents a novel, cross-entity therapeutic regimen and offers a promising treatment avenue for rare, surgically challenging IDH-mutant gliomas.
Glioblastoma multiforme (GBM) is an extremely virulent and treatment-resistant primary brain tumor that has a very rapid course, is commonly recurrent, and has very poor patient prognosis. Discovery of strong molecular targets is still urgent to further precision oncology in GBM. An integrative bioinformatics and computational platform was used to clarify oncogenic applicability and druggability of ribonucleotide reductase subunit M2 (RRM2) in the current study. The clinical value of RRM2 is demonstrated by the significant up-regulation in GBM in both cases of differential expression and survival analysis to accompany the poor prognostic outcome. Functional enrichment studies also highlighted its role in key oncogenic pathways, such as cell cycle, DNA replication, and nucleotide biosynthesis. These were followed by structure-based virtual screening against three validated binding sites of RRM2, which showed that several phytochemicals had better binding affinities than known inhibitors. It is worth noting that nardostachysin, calactin, and oleanolic acid surfaced as promising candidates, and they showed good consistent interaction major functional domains. ADMET and toxicity profiling identified nardostachysin as the most promising lead compound, with the best pharmacokinetic properties and good safety parameters. Taken together, these data make RRM2 an attractive therapeutic candidate in GBM and suggest some phytochemicals as potential inhibitors. This paper provide a logical basis for further experimental validation and creation of new, plant-tailored therapeutic interventions to manage GBM.
S. Singh, Pardeep Yadav, S. K. Jha· Medicinal Plants - Internati...· 0 citations
BACKGROUND
Glioblastoma is the most aggressive primary malignant brain tumor of the central nervous system and remains difficult to treat because of rapid progression, diffuse invasion, and frequent recurrence. This study aimed to identify a potential natural compound against glioblastoma using a reverse network pharmacology strategy and to investigate its anti-glioma effects and underlying mechanism.
METHODS
Glioblastoma-related targets were collected from public disease databases and integrated with differentially expressed genes from a public transcriptomic dataset to identify intersecting targets. Protein-protein interaction analysis, hub target screening, functional enrichment analysis, and reverse network pharmacology were performed to identify candidate compounds. Molecular docking and 100-ns molecular dynamics simulations were used to assess interactions between 20-hydroxyecdysone and pathway-related targets. Cell viability, colony formation, apoptosis, migration, and protein expression were examined in U251 and U87 glioma cells. Statistical differences were analyzed using a paired Student's t-test for two-group comparisons or one-way analysis of variance (ANOVA) followed by Dunnett's multiple-comparisons test for multi-group comparisons, as appropriate.
RESULTS
A total of 136 intersecting targets and 18 hub targets were identified. Functional enrichment analysis indicated that the phosphatidylinositol 3-kinase/protein kinase B signaling pathway was one of the key enriched pathways. Reverse network pharmacology identified 20-hydroxyecdysone as a candidate compound. Molecular docking showed relatively strong binding of 20-hydroxyecdysone to epidermal growth factor receptor, fms-related receptor tyrosine kinase 1, and integrin subunit alpha 5, and molecular dynamics simulations supported the stability of these complexes. In vitro experiments showed that 20-hydroxyecdysone inhibited cell viability, clonogenicity, and migration, while promoting apoptosis. It also reduced the phosphorylation levels of phosphatidylinositol 3-kinase, protein kinase B, and glycogen synthase kinase 3 beta at Ser9 without markedly altering total protein expression.
CONCLUSION
Treatment with 20-Hydroxyecdysone showed anti-glioma activity in vitro and may exert its effects, at least in part, through suppression of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway. These findings support its further evaluation as a potential therapeutic candidate for glioblastoma.
Unknown authors· Frontiers in Bioscience· 0 citations
Isocitrate dehydrogenase (IDH) enzyme system plays a central role in cellular metabolism, growth, and differentiation, and its mutations are associated with alterations of the cell cycle and production of oncometabolites, promoting tumor development. In this narrative review, we provide an overview of the current evidence on the therapeutic use of IDH inhibitors in IDH mutant gliomas and gastrointestinal cancers, focusing on cholangiocarcinoma (CCA) and colorectal cancer (CRC). Recent clinical studies showed promising data for IDH-targeted therapy in reducing tumor volume and led to the Food and Drug Administration (FDA) approval of ivosidenib for previously treated metastatic biliary tract cancers and vorasidenib for patients with IDH mutant low-grade gliomas following surgery. In addition, we discuss the emerging, although still limited, evidence regarding IDH mutations in colorectal cancer. Herein, we describe the characteristics of the FDA-approved and other investigational IDH-targeted drugs, evaluating the most recent clinical studies on targeting IDH genomic alterations in the treatment of gliomas and cholangiocarcinoma; we also provide insight into factors involved in resistance to IDH inhibition and potential strategies to overcome resistance mechanisms. Finally, we examine the major challenges facing IDH targeted therapy, including primary and acquired resistance, while highlighting future research directions such as next-generation IDH inhibitors, combination strategies, potential biomarkers, and the integration of molecular profiling into precision oncology to improve clinical outcomes.
Virginia Agnetti, Alessandro Acunzo, Giulia Airò et al.· Discover medicine· 0 citations
This multi-layered computational investigation suggests that S. anacardium contains phytochemicals with computationally predicted interactions targeting HSP90AA1-associated pathways implicated in brain tumors, and identifies HSP90AA1 as a putative target for future experimental investigation for natural product-guided anti-brain tumor strategies.
I. U. Haq, Abbas Khan, S. Saleem et al.· Network Modeling Analysis in...· 0 citations
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