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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
Author(s) -
Poonan Preantha,
Agoni Clement,
Soliman Mahmoud E. S.
Publication year - 2021
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.202100110
Subject(s) - chemistry , glioma , mutant , biophysics , docking (animal) , isocitrate dehydrogenase , knockout mouse , binding site , enzyme , stereochemistry , computational biology , biochemistry , cancer research , receptor , biology , gene , medicine , nursing
Recently, Vorasidenib (AG‐881) has been reported as a therapeutic alternative that exerts potent dual inhibitory activity against m IDH1/2 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 m IDH1 and m IDH2 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 m IDH1 and m IDH2, respectively. Interestingly, upon binding, AG‐881 was found to trigger systemic alterations of m IDH1 and m IDH2 characterized 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.