QSAR, ADME-Tox, molecular docking and molecular dynamics simulations of novel selective glycine transporter type 1 inhibitors with memory enhancing properties

Abstract

A structural class of forty glycine transporter type 1 (GlyT1) inhibitors, was examined using molecular modeling techniques. The quantitative structure-activity relationships (QSAR) technology confrmed that human GlyT1 activity is strongly and signifcantly affected by constitutional, geometrical, physicochemical and topological descriptors. ADME-Tox in-silico pharmacokinetics revealed that L28 and L30 ligands were predicted as non-toxic inhibitors with a good ADME profle and the highest probability to penetrate the central nervous system (CNS). Molecular docking results indicated that the predicted inhibitors block GlyT1, reacting specifically with Phe319, Phe325, Tyr123, Tyr 124, Arg52, Asp475, Ala117, Ala479, Ile116 and Ile483 amino acids of the dopamine transporter (DAT) membrane protein. These results were qualifed and strengthened using molecular dynamics (MD) study, which affrmed that the established intermolecular interactions for (L28, L30–DAT protein) complexes remain perfectly stable along 50 ns of MD simulation time. Therefore, they could be strongly recommended as therapeutics in medicine to improve memory performance.