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Dual-Knockout of Mutant Isocitrate Dehydrogenase 1 and 2 Subtypes towards Glioma Therapy: Structural Mechanistic insights on the role of Vorasidenib.

Mutant isocitrate dehydrogenase enzymes 1 and 2 (mIDH1/2) are reported to competitively trigger the conversion of alpha ketoglutarate (αKG) in the presence of NADPH, into 2-hydroxyglutarate (2-HG), an oncogenic stimulator. Although some available FDA-approved drugs have been successful in targeting the mIDH1 and mIDH2, their limited brain penetration capabilities have resulted in a low potential efficacy against glioma. Recently, Vorasidenib (AG-881) has been reported as a therapeutic alternative that exerts potent dual inhibitory activity against mIDH1/2 towards the treatment of low-grade glioma. However, structural and dynamic events associated with its dual inhibition mechanism remain unclear. As such, we employ integrative computer-assisted atomistic techniques to provide thorough structural and dynamic insights. Our analysis proved that the dual-targeting ability of AG-881 is mediated by Val255/Val294 within the binding pockets of both mIDH1 and mIDH2 which are shown to elicit a strong intermolecular interaction, thus favoring binding affinity. The structural orientations of AG-881 within the respective hydrophobic pockets allowed favorable interactions with binding site residues which accounted for its high binding free energy of -28.69 kcal/mol and -19.89 kcal/mol towards mIDH1 and mIDH2, respectively. Interestingly, upon binding, AG-881 was found to trigger systemic alterations of mIDH1 and mIDH2 characterised by restricted residue flexibility and a reduction in exposure of residues to the solvent surface area. As a result of these structural alterations, crucial interactions of the mutant enzymes were inhibited, a phenomenon that results in a suppression of the production of oncogenic stimulator 2-HG. Findings therefore provide thorough structural and dynamic insights associated with the dual inhibitory activity of AG-881 towards glioma therapy.