Discovery of novel Glutaminase allosteric inhibitors through drug repurposing and comparative MMGB/PBSA and molecular dynamics simulation

GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining prominence as a target for tumor treatment including lung, breast, kidney, prostate, and colorectal. To date, several medicinal chemistry studies are being conducted to develop new and effective inhibitors against GLS1 enzymes. Telaglenastat, a drug that targets the allosteric site of GLS1, has undergone clinical trials for the first time for the therapy of solid tumors and hematological malignancies. A comprehensive computational investigation is performed to get insights into the inhibition mechanism of the Telaglenastat. Some novel inhibitors are also proposed against GLS1 enzymes using the drug repurposing approach using 2D-fingerprinting virtual screening method against 2.4 million compounds, application of pharmacokinetics, Molecular Docking, and Molecular Dynamic (MD) Simulations. A TIP3P water box of 10 Å was defined to solvate both enzymes to improve MD simulation reliability. The dynamics results were validated further by the MMGB/PBSA binding free energy method, RDF, and AFD analysis. Results of these computational analysis revealed a stable binding affinity of Telaglenastat, as well as an FDA approved drug Astemizole (IC₅₀ ∼ 0.9 nM) and a novel para position oriented methoxy group containing Chembridge compound (Chem-64284604) that provides an effective inhibitory action against GAC and KGA.