Background: The human monoamine transporters (hMATs) primary 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 database 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.
Keywords: Monoamine transporters, allosteric modulation, multi-target drug, common binding mode, drug selectivity, computational modeling, structure activity analysis
Rights & PermissionsPrintExport