A Novel Bromine-Containing Paroxetine Analogue Provides Mechanistic Clues for Binding Ambiguity at the Central Primary Binding Site of the Serotonin Transporter.
A Novel Bromine-Containing Paroxetine Analogue Provides Mechanistic Clues for Binding Ambiguity at the Central Primary Binding Site of the Serotonin Transporter.
复制标题
一种新型含溴帕罗西汀类似物为血清素转运蛋白中央主要结合位点的结合模糊性提供了机制线索。
DOI：
10.1021/acschemneuro.9b00375
复制
发表时间：
2019
影响因子：
5
通讯作者：
Shi,Lei
中科院分区：
文献类型：
--
作者：
Slack,RachelD;Abramyan,AraM;Tang,Helen;Meena,Sitaram;Davis,BruceA;Bonifazi,Alessandro;Giancola,JoLynnB;Deschamps,JeffreyR;Naing,Sett;Yano,Hideaki;Singh,SatinderK;Newman,AmyHauck;Shi,Lei
5-羟色胺转运体（SERT）是选择性5-羟色胺再摄取抑制剂（SSRIs）的主要靶点。然而，广泛处方的SSRI、帕罗西汀与人SERT（hSERT）的非常高的结合亲和力的结构基础尚未完全阐明。我们以前的研究结果揭示了帕罗西汀的结合方向可能构成一个不可分割的组成部分，这种SSRI的高亲和力hSERT的一个合理的模糊性。在此，我们通过修饰配体和蛋白质来研究帕罗西汀高亲和力的因素。我们生成了一系列含溴（Br）的衍生物，并发现其中帕罗西汀的4-F被化学上类似但更富电子的Br原子（13）取代的衍生物具有最高的亲和力。通过比较帕罗西汀和13与野生型（WT）和在结合腔中含有帕罗西汀敏感突变的构建体的结合特征，我们确定了负责帕罗西汀的姿势模糊性的机制决定因素，这可以指导未来的药物设计。
The serotonin transporter (SERT) is the primary target for the selective serotonin reuptake inhibitors (SSRIs). However, the structural basis for the extraordinarily high binding affinity of the widely prescribed SSRI, paroxetine, to human SERT (hSERT) has not yet been fully elucidated. Our previous findings unveiled a plausible ambiguity in paroxetine’s binding orientations that may constitute an integral component of this SSRI’s high affinity for hSERT. Herein, we investigate factors contributing to paroxetine’s high affinity by modifying both the ligand and the protein. We generated a series of bromine (Br)-containing derivatives and found that the one in which the 4-F of paroxetine had been replaced with the chemically similar but more electron-rich Br atom (13) had the highest affinity. By comparatively characterizing the binding of paroxetine and13to both wild type (WT) and a construct harboring a paroxetine-sensitive mutation in the binding cavity, we identified a mechanistic determinant responsible for the pose ambiguity of paroxetine, which can guide future drug design.