Focus on Human Monoamine Transporter Selectivity. New Human DAT and NET Models, Experimental Validation, and SERT Affinity Exploration,ACS Chemical Neuroscience

当前位置： X-MOL 学术 › ACS Chem. Neurosci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Focus on Human Monoamine Transporter Selectivity. New Human DAT and NET Models, Experimental Validation, and SERT Affinity Exploration
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-09-29 , DOI: 10.1021/acschemneuro.0c00304
Gabriella Ortore ₁ , Elisabetta Orlandini _{2,

3} , Laura Betti ₁ , Gino Giannaccini ₁ , Maria Rosa Mazzoni ₁ , Caterina Camodeca ₁ , Susanna Nencetti ₁

Affiliation

The most commonly used antidepressant drugs are the serotonin transporter inhibitors. Their effects depend strongly on the selectivity for a single monoamine transporter compared to other amine transporters or receptors, and the selectivity is roughly influenced by the spatial protein structure. Here, we provide a computational study on three human monoamine transporters, i.e., DAT, NET, and SERT. Starting from the construction of hDAT and hNET models, whose three-dimensional structure is unknown, and the prediction of the binding pose for 19 known inhibitors, 3D-QSAR models of three human transporters were built. The training set variability, which was high in structure and activity profile, was validated using a set of in-house compounds. Results concern more than one aspect. First of all, hDAT and hNET three-dimensional structures were built, validated, and compared to the hSERT one; second, the computational study highlighted the differences in binding site arrangement statistically correlated to inhibitor selectivity; third, the profiling of new inhibitors pointed out a conservation of the inhibitory activity trend between rabbit and human SERT with a difference of about 1 order of magnitude; fourth, binding and functional studies confirmed 4-(benzyloxy)-4-phenylpiperidine 20a–d and 21a–d as potent SERT inhibitors. In particular, one of the compounds (compound 20b) revealed a higher affinity for SERT than paroxetine in human platelets.

中文翻译：

专注于人类单胺转运蛋白的选择性。新的人类 DAT 和 NET 模型、实验验证和 SERT 亲和力探索

最常用的抗抑郁药物是血清素转运蛋白抑制剂。与其他胺转运蛋白或受体相比，它们的作用在很大程度上取决于单个单胺转运蛋白的选择性，并且选择性大致受空间蛋白质结构的影响。在这里，我们对三种人类单胺转运蛋白（即 DAT、NET 和 SERT）进行了计算研究。从构建三维结构未知的hDAT和hNET模型开始，预测19种已知抑制剂的结合位姿，构建了三种人体转运蛋白的3D-QSAR模型。使用一组内部化合物验证了结构和活性高的训练集可变性。结果涉及不止一个方面。首先搭建hDAT和hNET三维结构，经过验证，并与 hSERT 进行比较；其次，计算研究强调了与抑制剂选择性统计相关的结合位点排列的差异；第三，新抑制剂的分析表明兔和人SERT之间的抑制活性趋势保持不变，差异约为1个数量级；四、结合和功能研究证实4-(苄氧基)-4-苯基哌啶20a-d和21a-d作为有效的 SERT 抑制剂。特别是，其中一种化合物（化合物20b）在人类血小板中显示出对 SERT 的亲和力高于帕罗西汀。

更新日期：2020-10-21

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11