Structure-Based Search for Novel Creatine Transporter Inhibitors

Creatine transporter 1 (CT1, SLC6A8) regulates cellular energy levels. Mutations in CT1 cause severe neurological disorders, whereas CT1 overexpression has been associated with cancer progression. Rational development of CT1 inhibitors has been limited by the absence of structural data. Here, we constructed homology models of CT1 representing distinct transport states and integrated them into a structure-based virtual screening workflow. From this approach, 16 top-ranked compounds were tested in vitro. Among them, compound 11 showed inhibitory activity with an IC50 comparable to the reference ligand ompenaclid. We demonstrate that tiagabine (13) and its analogue 16 also inhibit CT1. Following the completion of this study, cryo-EM structures of CT1 were reported. Retrospective comparison confirmed good agreement between our models and the experimental structures. These findings provide a computational–experimental framework for CT1 inhibitor discovery and support future structure-based drug design.