Exploration of insights, opportunities and caveats provided by the X-ray structures of hSERT

详细信息    查看全文

• 作者：Sid Topiol^a ; ^{sid.topiol@3D-2drug.com" class="auth_mail" title="E-mail the corresponding author} ; Benny Bang-Andersen^b ; Connie Sanchez^c ; Klaus P. B&oslash ; ges&oslash ; ^d
• 关键词：SERT ; serotonin transporter ; DAT ; dopamine transporter ; NAT ; noradrenaline transporter ; NSS ; neurotransmitter sodium transporters ; SSRI ; selective serotonin reuptake inhibitor ; TCA ; tricyclic antidepressant ; drosoph. ; Drosophila melanogaster ; LeuT ; leucine transporter
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：26
• 期：20
• 页码：5058-5064
• 全文大小：1656 K

文摘

The recently reported X-ray structures of the human serotonin (5-HT) transporter SERT with bound inhibitors open new opportunities for drug discovery at SERT, selectivity design with respect to other neurotransmitter sodium transporters, and enhanced understanding of the molecular events involved in SERT action. Through computational and structural analyses, we explore the binding and migration of 5-HT at SERT. Consistent with earlier studies of leucine migration at the bacterial homolog of SERT, LeuT, we find multiple potential ‘stopover’ sites for 5-HT binding at SERT including the two (transmembrane S1 and extracellular vestibule S2) seen in the binding of the SSRI (S)-citalopram (S-Cit) to SERT, as well as other sites. Docking studies reveal the possibility of both hetero- (S-Cit + 5-HT) and homo-dimeric (5-HT + 5-HT) co-binding at both these sites which may explain earlier published allosteric activity observations and provide novel design strategies. Comparisons with substrate bound X-ray structures of the dopamine transporter reveal a number of potential sources of selectivity, some of which may be ‘artificial’ including target based, species related, experimental design related, and ligand dependent examples including substrate versus inhibitor related features.