Koldsø Heidi, Grouleff Julie, Schiøtt Birgit
Department of Biochemistry, University of Oxford , Oxford, UK ; inSPIN and iNANO Centers, Department of Chemistry, Aarhus University , Aarhus C, Denmark.
inSPIN and iNANO Centers, Department of Chemistry, Aarhus University , Aarhus C, Denmark.
Front Pharmacol. 2015 Sep 24;6:208. doi: 10.3389/fphar.2015.00208. eCollection 2015.
Understanding of drug binding to the human biogenic amine transporters (BATs) is essential to explain the mechanism of action of these pharmaceuticals but more importantly to be able to develop new and improved compounds to be used in the treatment of depression or drug addiction. Until recently no high resolution structure was available of the BATs and homology modeling was a necessity. Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling. Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT. The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.
了解药物与人源生物胺转运体（BATs）的结合对于解释这些药物的作用机制至关重要，但更重要的是能够开发出用于治疗抑郁症或药物成瘾的新型改良化合物。直到最近，还没有BATs的高分辨率结构，同源建模成为必要手段。各种研究已经通过同源建模揭示了众多配体与BATs的经实验验证的结合模式。在此，我们研究并讨论了人源BATs同源模型中底物、抗抑郁药、精神兴奋剂和马吲哚的结合模型与最近发表的果蝇多巴胺转运体和工程化蛋白LeuBAT的晶体结构之间的相似性。比较结果表明，结合实验数据进行仔细的计算建模可用于预测分子与蛋白质的结合，且预测结果与晶体结构非常吻合。
