Exploration of Bacopa monnieri-derived Green Ligands for Targeted IDH1 Inhibition in Glioblastoma.

Abstract

Background: Sustainable drug discovery is an emerging paradigm in biomedicine driven by green chemistry principles, which allow mindful utilization of favorable renewable biological scaffolds and energy-efficient computational strategies. Plant-derived phytochemicals represent an ecologically reliable alternative to conventional synthetic drug libraries, consistent with the principles of low-carbon use and resource-effective innovation. In this study, phytocompounds from Bacopa monnieri were screened against wild-type and mutant Isocitrate Dehydrogenase 1 (IDH1), which is a key enzyme involved in glioblastoma pathogenesis.

Method: This study employed a comprehensive, multi-layered computational approach comprising Protein-Protein Interaction (PPI) networks and Gene Ontology (GO) annotations, KEGG pathway enrichment, molecular docking, ADME profiling, and Molecular Dynamics (MD) simulations.

Result: The network analysis revealed that IDH1, IDH3A, IDH3B, CS, and OGDH were identified as major regulators of oncogenic metabolic pathways. Further, enrichment analysis associated these proteins with key processes involved in tumor metabolism and redox regulation. Molecular docking identified Bacoside A2 as the most favorable compound with high affinity for wild-type and mutant IDH1's catalytic residues, followed by Bacopaside VII. MD simulation studies confirmed that Bacoside A2 forms a stable, energetically favorable complex within the catalytic pocket, which remained consistent throughout the simulation. In addition to its potential medical applications, this computational based phytochemical study reflects the principles of green energy and green chemistry by combining renewable plant-based scaffolds with energy-efficient in silico techniques, thereby greatly reducing laboratory resource consumption.

Discussion: The integrated system-level network analysis, combined with computational docking and molecular dynamics studies, supported the feasibility of using the renewable phytochemical scaffold, Bacoside A2, as a potential dual inhibitor of IDH1 in central nervous system tumors.

Conclusion: Bacoside A2 emerges as a strong, nanotechnologically versatile phytocompound and a dual IDH1 inhibitor, with potential for use in the development of next-generation, natural product-based therapies against glioblastoma and other malignancies associated with IDH1.