Exploring drug repurposing for SGK1 inhibition: FDA-approved drugs and structural insights for new therapeutic strategies

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that plays a crucial role in various cellular functions, including cell growth, regulation of ion channels, and immune response. The aberrant expression of SGK1 is linked to numerous diseases, such as cancer, cardiovascular diseases, and neurological disorders, which makes it a potential target for drug development. Nevertheless, the development of effective SGK1-targeted therapies has been a major challenge due to drug resistance and off-target side effects. In the present study, we employed a structure-based approach for drug repurposing to identify potential SGK1 inhibitors among 3648 FDA-approved drugs obtained from DrugBank. Using molecular docking, virtual screening, and 500 ns molecular dynamics (MD) simulations, we explored the potential of these drugs as SGK1 modulators. The results led to the identification of two high-confidence lead candidates, Venetoclax and Lanreotide, that were predicted to bind optimally while remaining stably docked within the SGK1 active site. Representative binding patterns were observed between SGK1 and targeted compounds (Venetoclax and Lanreotide) that have been previously tested in clinical settings with reference inhibitors. The drug profiles demonstrate potential repurposed roles in conjunction with drug development associated with SGK1. In summary, this study demonstrates the value of structure-guided drug repurposing in discovering SGK1 inhibitors and highlights the translational potential of the obtained compounds, particularly Venetoclax and Lanreotide. These findings provide a foundation for future experimental validation and therapeutic development of novel strategies targeting SGK1 to treat multiple pathological processes. • Virtual screening identified SGK1 inhibitors from FDA-approved drugs. • Lanreotide shows stable binding and strong interactions with SGK1. • Venetoclax exhibits high affinity toward the SGK1 active site. • MD simulations confirm stability of SGK1–ligand complexes. • Drug repurposing offers a strategy for SGK1-targeted therapy.