Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Abstract Neomorphic transformation in isocitrate dehydrogenase 1 (IDH1) are the key mutations prevalently found in various cancers including glioma. Recently identified mIDH1 specific inhibitors such as ivosidenib and Vorasidenib were restricted for use due to its modest brain penetrating potential and dose limiting toxicity respectively. Herein, we elucidate integrated virtual screening strategies to discover persuasive mIDH1 inhibitors from the approved subset of the DrugBank database consisting of 2715 molecules. Initially, structural similarity search identified a total of 1432 lead molecules. The resultant compounds were inspected by molecular docking along with MM-GBSA and ADMET analyses. Altogether, the analyses identified DB12001 (Abemaciclib) as the hit against mIDH1. Notably, Abemaciclib was able to form hydrogen bond interaction with active site residues of mIDH1 protein. In the end, the dynamic behavior of the hit complex was also examined using molecular dynamic (MD) simulation studies. The outcome of the study culminates that the hit complex was stable throughout the simulation period of 100ns. It is worth noting that benzimidazole moiety of Abemaciclib was reported to show inhibitory activity against glioma cells. Overall, these findings highlight that DB12001 has the potential as lead molecule against glioma. Indeed the screened hit compound could be further explored for the development of mIDH1 inhibitor with great brain penetrating ability and low toxicity.