Structural Determinants of the Neuronal Glycine Transporter 2 for the Selective Inhibitors ALX1393 and ORG25543.
Structural Determinants of the Neuronal Glycine Transporter 2 for the Selective Inhibitors ALX1393 and ORG25543.
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选择性抑制剂ALX1393和ORG25543的神经元甘氨酸转运蛋白2的结构决定因素。
DOI：
10.1021/acschemneuro.0c00602
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发表时间：
2021-06-02
影响因子：
5
通讯作者：
López-Corcuera B
中科院分区：
文献类型：
--
作者：
Benito-Muñoz C;Perona A;Felipe R;Pérez-Siles G;Núñez E;Aragón C;López-Corcuera B
神经元甘氨酸转运蛋白GlyT 2通过控制突触甘氨酸的细胞外浓度和神经递质向突触前末梢的供应来调节抑制性甘氨酸能神经传递。存在于背角中的脊髓甘氨酸能神经元在病理性疼痛条件下降低其活性，并充当触摸疼痛回路的门控者。GlyT 2的药理学阻断通过增加甘氨酸细胞外水平来减少疼痛信号向中枢神经系统嘴侧区域的进展，因此其具有镇痛作用。O-[（2-苄氧基苯基-3-氟苯基）甲基]-l-丝氨酸（ALX 1393）和N-[[1-（二甲基氨基）环戊基]甲基]-3，5-二甲氧基-4-（苯基甲氧基）苯甲酰胺（ORG 25543）是两种选择性GlyT 2抑制剂，在疼痛动物模型中对转运蛋白和镇痛作用具有纳摩尔亲和力，但存在妨碍进一步临床开发的缺陷。在这份报告中，我们进行了ALX 1393和ORG 25543的比较配体对接的验证GlyT 2结构模型，包括所有的配体位点构建的同源性与结晶多巴胺转运蛋白从果蝇。分子动力学模拟和能量分析的复杂性和功能分析的一系列点突变体允许确定的结构决定因素的ALX 1393和ORG 25543的歧视GlyT 2。配体与跨膜结构域1、3、6和8中存在的残基建立同时接触，并以外向构象阻断转运蛋白，从而抑制甘氨酸转运。此外，ALX 1393与Na 1位点结合的阳离子以及ORG 25543与TM 10的差异相互作用定义了抑制剂的差异位点，并解释了它们的一些个体特征。与GlyT 2相互作用的结构信息可能为新药发现提供有用的工具。
The neuronal glycine transporter GlyT2 modulates inhibitory glycinergic neurotransmission by controlling the extracellular concentration of synaptic glycine and the supply of neurotransmitter to the presynaptic terminal. Spinal cord glycinergic neurons present in the dorsal horn diminish their activity in pathological pain conditions and behave as gate keepers of the touch-pain circuitry. The pharmacological blockade of GlyT2 reduces the progression of the painful signal to rostral areas of the central nervous system by increasing glycine extracellular levels, so it has analgesic action. O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-l-serine (ALX1393) and N-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-(phenylmethoxy)benzamide (ORG25543) are two selective GlyT2 inhibitors with nanomolar affinity for the transporter and analgesic effects in pain animal models, although with deficiencies which preclude further clinical development. In this report, we performed a comparative ligand docking of ALX1393 and ORG25543 on a validated GlyT2 structural model including all ligand sites constructed by homology with the crystallized dopamine transporter from Drosophila melanogaster. Molecular dynamics simulations and energy analysis of the complex and functional analysis of a series of point mutants permitted to determine the structural determinants of ALX1393 and ORG25543 discrimination by GlyT2. The ligands establish simultaneous contacts with residues present in transmembrane domains 1, 3, 6, and 8 and block the transporter in outward-facing conformation and hence inhibit glycine transport. In addition, differential interactions of ALX1393 with the cation bound at Na1 site and ORG25543 with TM10 define the differential sites of the inhibitors and explain some of their individual features. Structural information about the interactions with GlyT2 may provide useful tools for new drug discovery.
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影响因子：
64.8
作者：
Coleman, Jonathan A.;Yang, Dongxue;Gouaux, Eric
通讯作者：
Gouaux, Eric
影响因子：
4.8
作者：
Arribas-Gonzalez, Esther;de Juan-Sanz, Jaime;Lopez-Corcuera, Beatriz
通讯作者：
Lopez-Corcuera, Beatriz
影响因子：
56.9
作者：
MELZACK, R;WALL, PD
通讯作者：
WALL, PD
影响因子：
5.7
作者：
Haranishi, Yasunori;Hara, Koji;Sata, Takeyoshi
通讯作者：
Sata, Takeyoshi
影响因子：
5.5
作者：
Bradaïa, A;Schlichter, R;Trouslard, J
通讯作者：
Trouslard, J