Identification of novel GPX4 inhibitors from bioactive compounds of Tinospora cordifolia: An in-silico study

In recent years, ferroptosis, a new form of regulated cell death mechanism, has attracted significant attention in cancer therapy. This pathway is negatively regulated by an enzyme glutathione peroxidase 4 (GPX4). Thus, targeting this enzyme offers an innovative approach for cancers which are resistant to conventional treatment. This study aims to identify selected alkaloid compounds of Tinospora cordifolia with excellent ADMET characteristics to find possible GPX4 inhibitors. The alkaloids of T. cordifolia were compiled from PubChem database and screened for drug likeliness and ADMET properties. ADMET analysis and Lipinski’s rule of five showed that most of the compounds generally possess favorable pharmacokinetic properties. The CB Dock2 tool was used to evaluate the binding affinities of alkaloids with target protein GPX4. The binding free energies for berberine, palmatine, magnoflorine, jatrorrhizine, and tetrahydropalmatine were -7.0, -6.8, -7.1, -6.7, and -6.4 kcal/mol, respectively. Among the selected alkaloids of T. cordifolia, magnoflorine is the most effective GPX4 inhibitor with a binding affinity of -7.1 kcal/mol. These findings suggest that magnoflorine can be considered as a potential anticancer agent by targeting emerging targets like GPX4 but require further in-vitro and in-vivo experimental validation.