Study on the Unbinding of Triple Reuptake Inhibitor from Monoamine Transporters by Steered Molecular Dynamics Simulations

OBJECTIVE To investigate the unbinding mechanism between triple reuptake inhibitors(TRIs) and human monoamine transporters(hMATs). METHODS Steered molecular dynamics was used to explore the unbinding process of three inhibitors from hSERT, hNET and hDAT. The important protein-ligand interactions during dissociation were analyzed by calculating the external force-time profiles. Finally, the results of potential of mean force of the three inhibitors in each transporter were calculated by using the second cumulant expansion of Jarzynski’s equality. RESULTS The force-time curve indicated that residues located in transmembrane domains(TM1b, TM3, TM6a and TM10) and extracellular loops domains(EL2, EL4, EL5 and EL6) were mainly involved in the ligand unbinding. The residues were located on the center binding site of protein could greatly hinder ligand dissociation. The average power potential of each system was computed and the result denoted that the dissociation of EB1020 from the hMATs was easier than that of NS2359 and SEP225289. CONCLUSION This study reveals the unbinding dissociation mechanism of hMATs and TRIs at the atomic level, which provides a theoretical basis for structure-based antidepressant drug design with higher potency and selectivity.