Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET
Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET
复制标题
DOI：
10.1073/pnas.1106030108
复制
发表时间：
2011-09-20
影响因子：
11.1
通讯作者：
Sali, Andrej
中科院分区：
文献类型：
--
作者：
Schlessinger, Avner;Geier, Ethan;Sali, Andrej
去甲肾上腺素转运蛋白（NET）将去甲肾上腺素从突触转运到突触前神经元，其中去甲肾上腺素通过与各种受体结合来调节与心血管效应和行为特征相关的信号通路（例如，例如，在一个实施例中，β 2-肾上腺素能受体）。NET是多种处方药（包括抗抑郁药和精神兴奋剂）的已知靶点，并可能介导其他处方药的脱靶效应。在这里，我们确定处方药结合NET，使用虚拟配体筛选，然后通过实验验证预测配体。我们首先构建了一个比较结构模型NET的基础上对齐的原子结构的原核NET同系物，亮氨酸转运蛋白LeuT。通过确认已知的NET配体与非结合分子相比可以有利地对接来验证建模的结合位点。然后，我们根据NET模型计算筛选了来自京都基因和基因组百科全书（KEGG DRUG）的6，436种药物。在实验测试的18种高分药物中，有10种被发现是NET抑制剂;其中5种是NET的化学新型配体。这些结果可能合理的疗效几个交感神经（tuaminoheptane）和抗抑郁药（反苯环丙胺），以及副作用的糖尿病（phenylamine）和阿尔茨海默氏症（talsaclidine）药物。观察结果强调了针对比较模型进行虚拟筛选的实用性，即使目标与其模板结构的序列同一性低于30%并且主要结合位点中没有已知配体。
The norepinephrine transporter (NET) transports norepinephrine from the synapse into presynaptic neurons, where norepinephrine regulates signaling pathways associated with cardiovascular effects and behavioral traits via binding to various receptors (e. g., beta 2-adrenergic receptor). NET is a known target for a variety of prescription drugs, including antidepressants and psychostimulants, and may mediate off-target effects of other prescription drugs. Here, we identify prescription drugs that bind NET, using virtual ligand screening followed by experimental validation of predicted ligands. We began by constructing a comparative structural model of NET based on its alignment to the atomic structure of a prokaryotic NET homolog, the leucine transporter LeuT. The modeled binding site was validated by confirming that known NET ligands can be docked favorably compared to nonbinding molecules. We then computationally screened 6,436 drugs from the Kyoto Encyclopedia of Genes and Genomes (KEGG DRUG) against the NET model. Ten of the 18 high-scoring drugs tested experimentally were found to be NET inhibitors; five of these were chemically novel ligands of NET. These results may rationalize the efficacy of several sympathetic (tuaminoheptane) and antidepressant (tranylcypromine) drugs, as well as side effects of diabetes (phenformin) and Alzheimer's (talsaclidine) drugs. The observations highlight the utility of virtual screening against a comparative model, even when the target shares less than 30% sequence identity with its template structure and no known ligands in the primary binding site.