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.

背景：人类单胺转运蛋白（hMATs）主要包括hSERT，hNET和hDAT，是治疗抑郁症和其他行为障碍的重要靶标，其使用量超过30种已获批准的药物。

目的：本文综述了具有中心或变构结合位点的hMATs抑制剂的结合方式和抑制机理的最新进展，以利于将来hMATs抑制剂的设计和发现。将重点介绍通过体外和体内实验评估的结构-活性关系（SAR）和命中/先导化合物对hMATs的选择性。

方法：在PubMed和Web of Science数据库中搜索蛋白质-配体相互作用，新型抑制剂设计以及与hMAT相关的合成研究。

结果：文献数据表明，自与氯米帕明复合的同源细菌亮氨酸转运蛋白（LeuT）的首次晶体结构确定以来，已积累了超过100个实验结构或计算模型的可观数据库，现已定义了相当程度的结构变异性hMATs-配体识别。同时，在计算模型的显着帮助下，通过药物化学发现了许多新型的hMATs抑制剂。

结论：报道的新化合物通过实验或计算模型作用于hMATs以及与多种配体复合的转运蛋白的结构，为药物对转运蛋白的多药理学，多峰和变构调节提供了启示。所有这些研究都将极大地促进结构新颖的支架的基于结构的药物设计（SBDD），该支架对hMAT具有高活性和选择性。