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bioRxiv · 10.1101/510487

Discovery of New Classes of Glycine transporter 2 (GlyT2) Inhibitors and Study of GlyT2 Selectivity by Combination of Novel Structural Based Virtual Screening Approach and Free Energy Perturbation (FEP+) Calculations

Sirimulla, S.·Miranda-Arango, M.·Padilla, E.
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Abstract

In recent years, the mammalian GlyT2 transporter has emerged as a promising tar-get for the development of anti-chronic pain agents. In our current work, we discovered a new set of promising hits that inhibit the glycine transport 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. Furthermore, the free energy perturbation (FEP+ protocol) calculations and molecular dynamics (MD) studies revealed the GlyT2 amino acid residues critical for the binding and selectivity of both Glycine and our Lead1 compound. The FEP+ results well-matched available literature mutational data proving the quality of the generated GlyT2 structure. Based on these calculations we propose that Lead1 may also be a strong inhibitor of the neutral and basic amino acid transporter B (0+) (SLC6A14). Thus, the subsequent lead optimization and characterization of refined compounds may lead to both chronic pain and pancreatic cancer agents addressing an unmet and challenging clinical needs.

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Sirimulla, S., Miranda-Arango, M., Padilla, E.. 2019-01-04. Discovery of New Classes of Glycine transporter 2 (GlyT2) Inhibitors and Study of GlyT2 Selectivity by Combination of Novel Structural Based Virtual Screening Approach and Free Energy Perturbation (FEP+) Calculations. https://doi.org/10.1101/510487

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