Background: The human Monoamine Transporters (hMATs), primarily including hSERT,
hNET and hDAT, are important targets for the treatment of depression and other behavioral disorders
with more than the availability of 30 approved drugs.
Objective: This paper is to review the recent progress in the binding mode and inhibitory mechanism of
hMATs inhibitors with the central or allosteric binding sites, for the benefit of future hMATs inhibitor
design and discovery. The Structure-Activity Relationship (SAR) and the selectivity for hit/lead compounds
to hMATs that are evaluated by in vitro and in vivo experiments will be highlighted.
Methods: PubMed and Web of Science databases were searched for protein-ligand interaction, novel
inhibitors design and synthesis studies related to hMATs.
Results: Literature data indicate that since the first crystal structure determinations of the homologous
bacterial Leucine Transporter (LeuT) complexed with clomipramine, a sizable database of over 100 experimental
structures or computational models has been accumulated that now defines a substantial degree
of structural variability hMATs-ligands recognition. In the meanwhile, a number of novel hMATs
inhibitors have been discovered by medicinal chemistry with significant help from computational models.
Conclusion: The reported new compounds act on hMATs as well as the structures of the transporters
complexed with diverse ligands by either experiment or computational modeling have shed light on the
poly-pharmacology, multimodal and allosteric regulation of the drugs to transporters. All of the studies
will greatly promote the Structure-Based Drug Design (SBDD) of structurally novel scaffolds with high
activity and selectivity for hMATs.