Malignant gliomas account for the majority of the primary malignant brain tumors. The primary cause of glioma is missense mutations in isocitrate dehydrogenase 1 (IDH1). IDH1 mutations, especially R132H, which leads to heterodimerization, are implicated in gliomagenesis by altering cellular metabolism (Krebs cycle) and producing D-2-hydroxyglutarate (D-2-HG), an oncometabolite. This study explores natural compounds from traditional medicinal plants as potential inhibitors of the pathogenic IDH1 heterodimer. A virtual screening of a self-prepared library of 3000 phytocompounds was performed, and the best five ligands (according to binding score), namely alpha-amyrin acetate, diosgenin, strychnine, sesamolinol, and 13-cis-retinoic acid, were subjected to ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses. The molecular dynamics (MD) simulation (1000 ns) and MMPBSA calculation of the five ligands outlined above were carried out across a pH range of 1.2 to 7.6. All of the above experiments demonstrated that these ligands could inhibit the heterodimerization of IDH1, resulting in a reduction in the synthesis of D-2-HG and thereby restoring epigenetic balance. In particular, alpha-amyrin acetate and 13-cis-retinoic acid bound to a specific pocket that resides on the interface of the heterodimer (dimer of wild-type and IDH1_R132H), thereby hindering the dimerization more effectively. These compounds demonstrated robust binding affinity and complex stability, suggesting their potential to disrupt the aberrant metabolic pathway to suppress glioma formation. Ultimately, this study underscores the extraordinary potential and innovative strategies of harnessing medicinal plants and their phytochemicals as powerful anticancer agents against glioma.
