Discovery of GlyT2 Inhibitors Using Structure-Based Pharmacophore Screening and Selectivity Studies by FEP+ Calculations

© 2019 American Chemical Society. In recent years, mammalian Glycine transporter 2 (GlyT2) has emerged as a promising target for the development of compounds against chronic pain states. In our current work, we discovered a new set of promising hits that inhibit the glycine transporter at nano- and micromolar activity and have excellent selectivity over GlyT1 (as shown by in vitro studies) using a newly designed virtual screening (VS) protocol that combines a structure-based pharmacophore and docking screens with a success rate of 75%. Furthermore, the free energy perturbation calculations and molecular dynamics (MD) studies revealed the GlyT2 amino acid residues critical for the binding and selectivity of both Glycine and our Hit1 compound. The FEP+ results well-matched with the available literature mutational data proving the quality of the generated GlyT2 structure. On the basis of these results, we propose that our hit compounds may lead to new chronic pain agents to address unmet and challenging clinical needs