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

Mohamed El Fadili; Mohammed Er-Rajy; Hamada Imtara; Omar M Noman; Ramzi A Mothana; Sheaf Abdullah; Sara Zerougui; Menana Elhallaoui

doi:10.1016/j.heliyon.2023.e13706

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

Heliyon. 2023 Feb 13;9(2):e13706. doi: 10.1016/j.heliyon.2023.e13706. eCollection 2023 Feb.

Authors

Mohamed El Fadili¹, Mohammed Er-Rajy¹, Hamada Imtara², Omar M Noman³, Ramzi A Mothana³, Sheaf Abdullah⁴, Sara Zerougui¹, Menana Elhallaoui¹

Affiliations

¹ LIMAS Laboratory, Faculty of Sciences Dhar El Mehraz, Sidi Mohammed Ben Abdellah University, BP 1796 Atlas, Fez 30000, Morocco.
² Faculty of Arts and Sciences, Arab American University Palestine, Jenin BP Box 240, Palestine.
³ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁴ Department of Hand Surgery and Microsurgery, University Medicine Greifswald, Greifswald, Germany.

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 confirmed that human GlyT1 activity is strongly and significantly 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 profile 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 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.

Keywords: ADME-Tox; CNS; DAT; GlyT1; MD simulations; Molecular docking; QSAR.