Mitochondrial glutaminase (GLS1) is a key enzyme in glutaminolysis, essential for cellular energy and biosynthesis, and is implicated in diseases such as cancer and hepatic encephalopathy. In this study, we investigated the interaction of GLS1 with natural withanolides and known inhibitor using binding energy and intramolecular charge transfer analyses. Molecular docking focused on GLS1 subunits, particularly loop segments in chains B and D, using a homodimeric model (chains A and B) and GLS2 for docking studies. Both blind and site-specific docking approaches were applied and cross-validated. Compound 968 and BPTES showed the strongest inhibitory effects, followed by physapubesin, withanone, withanolide A, withaphysalin B and withaferin A. Molecular dynamics simulations confirmed the stability of the lead complexes, which were further evaluated for ADME properties. The study demonstrates that withanolides can stably target GLS1 and potentially modulate glutamine catabolism in the brain, suggesting hepatoprotective and neuroprotective relevance. Overall, these findings indicate that withanolides, particularly physapubesin and withanone, may serve as promising natural scaffolds for therapeutic interventions in hepatic encephalopathy.
Ramachandran et al. (Sun,) studied this question.