Identification of new IDH2 inhibitors by discriminatory analysis-based molecular docking and biological evaluation.

Isocitrate dehydrogenase 2 (IDH2) is a key enzyme in the regulation of cell metabolism. Its mutated type can lead to the accumulation of 2-hydroxyglutarate, which is often related to malignancies such as acute myeloid leukemia. Therefore, it is necessary to find new inhibitors targeting mutant IDH2. Discriminatory analysis-based molecular docking was employed to screen the ChemDiv compound library, which resulted in the identification of three new IDH2 inhibitors with moderate-to-good IC values. Among them, compounds 1 and 3 displayed good selectivity against other mutant or wild-type IDH proteins. The most potent compound 1, bearing the [1,2,4]triazolo[1,5-a]pyrimidin scaffold, was subjected to dynamic simulations to provide more information on the binding mode with IDH2 , providing structural clues to further optimize compound 1 as a new mutant IDH2 inhibitor.