Discovery of Novel IDH1 Inhibitor Through Comparative Structure-Based Virtual Screening

IDH1 mutations occur in about 20-30% of gliomas and are a promising target for the treatment of cancer. In the present study, the performance of aIDH1^R132H was verified via glide-docking-based virtual screening. On the basis of the two crystal structures (5TQH and 6B0Z) with the best discriminating ability to identify IDH1^R132H inhibitors from a decoy set, a docking-based virtual screening strategy was employed for identifying new IDH1^R132H inhibitors. In the end, 57 structurally diverse compounds were reserved and evaluated through experimental tests, and 10 of them showed substantial activity in targeting IDH1^R132H (IC₅₀ < 50 μM). Molecular docking technology showed that L806-0255, V015-1671, and AQ-714/41674992 could bind to the binding pocket composed of hydrophobic residues. These findings indicate that L806-0255, V015-1671, and AQ-714/41674992 have the potential as lead compounds for the treatment of IDH1-mutated gliomas through further optimization.