Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter.
Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter.
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DOI：
10.3389/fnmol.2017.00040
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发表时间：
2017
影响因子：
4.8
通讯作者：
Benn CL
中科院分区：
文献类型：
--
作者：
Choudhary P;Armstrong EJ;Jorgensen CC;Piotrowski M;Barthmes M;Torella R;Johnston SE;Maruyama Y;Janiszewski JS;Storer RI;Skerratt SE;Benn CL
除了运动功能受损之外，胆碱能功能减退还与中枢神经系统注意力下降和认知缺陷有关。因此，刺激胆碱能神经传递是潜在治疗各种神经系统疾病的合理治疗方法。乙酰胆碱 (ACh) 合成神经元的高亲和力胆碱摄取 (HACU) 关键由钠和 pH 依赖性高亲和力胆碱转运蛋白 (CHT，由 SLC5A7 基因编码) 介导。这种转运蛋白的特征相对较好，但作为潜在的药物靶点尚未被探索。因此，我们试图鉴定小分子，以验证 CHT 介导的转运的正调节将增强活性依赖性胆碱能信号传导的假设。我们利用现有的和新颖的筛选技术，利用文献工具揭示 CHT 的正向和负向调节。筛选活动以定制化合物库启动，其中包括辉瑞化学基因组库 (CGL) 中的 2,753 种分子，专门设计用于帮助阐明表型筛选中的新机制，以及来自虚拟筛选活动的 887 种化合物，以选择与报道的负变构调节剂和正变构调节剂具有基于现场的相似性的分子。我们鉴定了许多以前未知的活性且结构独特的分子，这些分子可用作进一步探索 CHT 生物学的工具或作为进一步药物化学的起点。
Cholinergic hypofunction is associated with decreased attention and cognitive deficits in the central nervous system in addition to compromised motor function. Consequently, stimulation of cholinergic neurotransmission is a rational therapeutic approach for the potential treatment of a variety of neurological conditions. High affinity choline uptake (HACU) into acetylcholine (ACh)-synthesizing neurons is critically mediated by the sodium- and pH-dependent high-affinity choline transporter (CHT, encoded by the SLC5A7 gene). This transporter is comparatively well-characterized but otherwise unexplored as a potential drug target. We therefore sought to identify small molecules that would enable testing of the hypothesis that positive modulation of CHT mediated transport would enhance activity-dependent cholinergic signaling. We utilized existing and novel screening techniques for their ability to reveal both positive and negative modulation of CHT using literature tools. A screening campaign was initiated with a bespoke compound library comprising both the Pfizer Chemogenomic Library (CGL) of 2,753 molecules designed specifically to help enable the elucidation of new mechanisms in phenotypic screens and 887 compounds from a virtual screening campaign to select molecules with field-based similarities to reported negative and positive allosteric modulators. We identified a number of previously unknown active and structurally distinct molecules that could be used as tools to further explore CHT biology or as a starting point for further medicinal chemistry.