Consensus virtual screening of approved and late-phase clinical drugs identifies candidate inhibitors of mutant IDH1 (R132H) for IDH-mutant glioma

Abstract

Background. Recurrent R132 mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) confer aneomorphic activity that reduces alpha-ketoglutarate to the oncometabolite D-2-hydroxyglutarate(2-HG), driving DNA and histone hypermethylation and defining a major subset of diffusegliomas. Inhibition of mutant IDH1 is clinically validated: vorasidenib became the first approvedtherapy for IDH-mutant grade 2 glioma, and enasidenib and ivosidenib are approved for IDHmutantacute myeloid leukemia (AML). Yet clinically explored chemotypes remain few, andapproved, brain-penetrant compounds that could be rapidly repositioned to mutant IDH1 are anuntapped resource. Methods. Using the Tomdok consensus virtual screening pipeline (companion preprint), wedocked 3,326 approved and Phase III compounds (ChEMBL 37, parent-deduplicated) against theallosteric pocket of IDH1 R132H (PDB 6VEI) with a three-engine consensus (GNINA,AutoDock Vina, LeDock), dual affinity/CNN-pose-confidence thresholds, and data-driven safetyannotation (hERG liability from ChEMBL KCNH2 bioactivity, PAINS, withdrawn status).Consensus strength was quantified as the number of engines scoring <= -9.0 kcal/mol; hits werestratified into CLEAN and FLAGGED classes. Results. The blind screen recovered, without prior knowledge, two clinically validated mutant-IDH inhibitors: vorasidenib, the co-crystallised ligand (triple-engine consensus; CNN 0.998),and enasidenib, an approved mutant-IDH2 inhibitor (top affinity, -11.84 kcal/mol) - a stronginternal validation. Self-docking reproduced the crystallographic pose (best-pose RMSD 0.45 A).Of 31 consensus hits, 20 were CLEAN and enriched in BBB-penetrant approved and late-phasecompounds, including the antiepileptic perampanel, the read-through agent ataluren, theserotonergic sarizotan, the SSRI dapoxetine, the PI3K delta/gamma inhibitor duvelisib, and theBcl-2 family antagonist obatoclax. The FLAGGED class (11 compounds) independently rederivedknown liabilities (hERG: celecoxib, lemborexant, mavorixafor; PAINS: quercetin,olsalazine). Conclusions. Consensus docking against IDH1 R132H is strongly validated by blind recovery oftwo approved mutant-IDH inhibitors and yields a shortlist of approved, brain-penetrantcandidates - led by perampanel and ataluren - for biochemical and cellular evaluation in IDHmutantglioma.