Exploration of natural product database for the identification of potent inhibitor against IDH2 mutational variants for glioma therapy

Abstract

Mutation in Isocitrate dehydrogenase 2 (mIDH2) is an oncogenic driver prevalently reported in various cancer types including gliomas. To date, enasidenib is the only FDA-approved drug widely used as a mIDH2 (R140Q) inhibitor. However, dose-limiting toxicity and modest brain penetrating capability restrict its use as a plausible mIDH2 inhibitor. Furthermore, secondary site mutations (Q316E and I319M) were identi ed in patients with enasidenib treatments resulting in acquired therapeutic resistance. Hence, in the present investigation, we aimed to identify novel and potent drug-like compounds to overcome the existing drawbacks using an integrated insilico strategy. A sum of 1574 natural compounds from the Naturally occurring Plant-based Anti-cancerous Compound Activity Target (NPACT) database was proclaimed and subjected to screening processes such as similarity calculations and molecular docking. The binding a nities of the resultant natural compounds were rescored using MM-GBSA and RF scoring functions. The toxicity and drug likeliness of the lead compounds were investigated using ADMET properties. Eventually, the integrated in-silico approach resulted in a lead molecule namely squalene (NPACT00954) against mIDH2 protein. The screened compound was subjected to mutational analysis accomplishing second-site mutations. Interestingly, squalene exhibited appreciable binding a nity alongside good brain penetrating potential than enasidenib. Indeed, the reproducibility and signi cance of our results are examined by running 3 replica 100ns simulations per system using the random initial velocities of the atoms generated by Maxwell distribution at a given temperature. Collectively, the results from our study speculate that squalene could be persuasively translated for its use as a rational therapeutic agent against mIDH2 variants.