Receptor-Based Discovery of a Plasmalemmal Monoamine Transporter Inhibitor via High Throughput Docking and Pharmacophore Modeling.
Receptor-Based Discovery of a Plasmalemmal Monoamine Transporter Inhibitor via High Throughput Docking and Pharmacophore Modeling.
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通过高通量对接和药效团建模基于受体发现质膜单胺转运蛋白抑制剂。
DOI：
10.1021/cn900032u
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发表时间：
2010-03-17
影响因子：
5
通讯作者：
Surratt, Christopher K.
中科院分区：
文献类型：
--
作者：
Indarte, Martin;Liu, Yi;Madura, Jeffry D.;Surratt, Christopher K.
多巴胺转运体(DAT)蛋白对可卡因和苯丙胺等精神刺激物的识别是与这些药物相关的快感和成瘾的主要原因。以远缘细菌亮氨酸转运蛋白的晶体结构为模板，建立了三维DAT计算机分子模型。与这种模型的配基对接揭示了潜在的底物和抑制剂结合口袋，随后被体外药理学证实。DAT模型定义的位于“细胞外前庭”内的抑制剂口袋，恰好在初级底物口袋的外门的细胞外侧，用于化合物结构文库的虚拟筛选。在这个前庭抑制剂口袋内的高通量对接和药效团限制的应用发现了一种在结构上不同于经典单胺(多巴胺、去甲肾上腺素和5-羟色胺)转运体(MAT)抑制剂的化合物。该化合物取代了放射性标记的可卡因类似物在所有三个垫子上的结合，通常具有纳摩尔KI值，并在可卡因与去甲肾上腺素转运体亲和力的两倍范围内。尽管这种化合物本身是一种非常弱的多巴胺摄取抑制剂，但在抑制DAT介导的细胞多巴胺摄取方面，这种化合物的效力是可卡因的三倍。据我们所知，目前的发现是第一次成功地使用“基于受体的”计算机建模来识别中到高亲和力的MAT配体。在硅胶配基筛选中，使用MAT模型提供了一个快速、低成本的发现过程，应该可以加速新的配基支架的鉴定，并在对抗精神刺激剂成瘾和治疗其他单胺相关的中枢神经系统疾病方面提供先导化合物。
Recognition of psychostimulants such as cocaine and the amphetamines by the dopamine transporter (DAT) protein is principally responsible for the euphoria and addiction associated with these drugs. Using as a template the crystal structure of a distantly related bacterial leucine transporter, 3-D DAT computer molecular models have been generated. Ligand docking to such models has revealed potential substrate and inhibitor binding pockets, subsequently confirmed by in vitro pharmacology. An inhibitor pocket defined by the DAT model to be within the “extracellular vestibule”, just to the extracellular side of the external gate of the primary substrate pocket, was used for virtual screening of a structural library of compounds. High-throughput docking and application of pharmacophore constraints within this vestibular inhibitor pocket identified a compound structurally dissimilar to the classic monoamine (dopamine, norepinephrine and serotonin) transporter (MAT) inhibitors. The compound displaced binding of radiolabeled cocaine analogs at all three MATs, usually with nanomolar Ki values and within two fold of cocaine's affinity at the norepinephrine transporter. Although a very weak dopamine uptake inhibitor itself, this compound reduced by three fold the potency of cocaine in inhibiting DAT-mediated cellular uptake of dopamine. To our knowledge, the present findings are the first to successfully employ “receptor-based” computer modeling to identify moderate-to-high affinity MAT ligands. In silico ligand screening using MAT models provides a rapid, low cost discovery process that should accelerate identification of novel ligand scaffolds and provide lead compounds in combating psychostimulant addiction and in treating other monoamine-related CNS diseases.
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DOI：
10.1124/jpet.106.106583
发表时间：
2006-11-01
影响因子：
3.5
作者：
Madras, Bertha K.;Xie, Zhihua;Fischman, Alan J.
通讯作者：
Fischman, Alan J.
影响因子：
5
作者：
Matsumoto, RR;Brackett, RL;Kanthasamy, AG
通讯作者：
Kanthasamy, AG
影响因子：
1.5
作者：
Que, XC;Brinen, LS;Reed, SL
通讯作者：
Reed, SL
DOI：
10.1016/j.bbrc.2004.06.155
发表时间：
2004-08-20
影响因子：
3.1
作者：
Rajnarayanan, RV;Dakshanamurthy, S;Pattabiraman, N
通讯作者：
Pattabiraman, N
影响因子：
7.3
作者：
Kazius, J;McGuire, R;Bursi, R
通讯作者：
Bursi, R