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

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.