Abstract
Serum and glucocorticoid-regulated kinase 1 (SGK1) is an underexplored kinase involved in several neurodegenerative diseases. Although SGK1 inhibitors are not available on the market, the absence of side effects in two SGK1 knockout mouse models supports the development of brain-penetrant SGK1 inhibitors to explore their therapeutic potential. Through a combined ligand- and target-based virtual screening using the ECBL, we identified a small heterocyclic molecule with SGK1 inhibitory activity (IC(50) = 0.66 ± 0.25 μM). Molecular dynamics simulations revealed two potential binding modes for the candidate compound, offering valuable insights for the further optimisation of this hit. The compound was predicted to be brain-permeable by both in silico methods and experimental assays. It also demonstrated a neuroprotective profile in a cellular model of Alzheimer's disease (AD) and showed a favourable cardiovascular safety profile. Finally, systems pharmacology analysis identified the FOXO1/FOXO3/CREB1 axis as the principal signalling pathway regulated by SGK1 in the context of AD.