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

A structural class of forty glycine transporter type 1 (GlyT1) inhibitors, was examined using molecular modeling techniques. The quantitative structure-activity relationships (QSAR) tech-nology confirmed that human GlyT1 activity is strongly and significantly affected by constitu-tional, 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 profile and the highest probability to penetrate the central nervous system (CNS). Molecular docking results indicated that the predicted inhibitors block GlyT1, reacting specif-ically 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 qualified and strengthened using molecular dynamics (MD) study, which affirmed 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.

Automated summary

A structural class of forty GlyT1 inhibitors was studied using molecular modeling techniques. QSAR analysis showed that human GlyT1 activity is influenced by various descriptors. In silico pharmacokinetics predicted that L28 and L30 are non-toxic inhibitors with good ADME profiles and high permeability through the CNS. Molecular docking and MD simulation confirmed the specific binding of the predicted inhibitors to key amino acids of DAT, suggesting their potential as therapeutics for memory improvement.