Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor.
Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor.
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DOI：
10.1016/j.bmcl.2017.10.068
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发表时间：
2017-12
影响因子：
2.7
通讯作者：
Xiaozhen Wang;Yuji Wang;Jianhui Wu;Lin Gui;Xiaoyi Zhang;Meiqing Zheng;Yaonan Wang;Shurui Zhao-Shurui-Z
中科院分区：
文献类型：
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作者：
Xiaozhen Wang;Yuji Wang;Jianhui Wu;Lin Gui;Xiaoyi Zhang;Meiqing Zheng;Yaonan Wang;Shurui Zhao-Shurui-Z
在GPIIb/IIIa介导的动脉血栓形成中，血小板活化起核心作用。为了发现血小板活化抑制剂，分析了GPIIb/IIIa受体抑制剂和抗血栓药物的药效团。这导致设计（1 R，3S）-和（1 S，3S）-1-甲基-1，2，3，4-四氢-β-咔啉-3-羧酸作为GPIIb/IIIa抑制剂。与（1 S，3S）-异构体相比，（1 R，3S）-异构体具有较低的cdocker相互作用能。AFM图像显示（1 S，3S）-异构体和（1 R，3S）-异构体抑制血小板活化的最小有效浓度分别为10− 5 M和10− 6 M;在体内，口服1 μmol/kg（1 S，3S）-异构体可有效抑制大鼠动脉血栓形成，下调GPIIb/IIIa表达，但活性明显低于口服1 μmol/kg（1 R，3S）-异构体。（1 S，3S）-异构体和（1 R，3S）-异构体均可安全地用于结构修饰，但（1 R，3S）-异构体应上级（1 S，3S）-异构体。
In GPIIb/IIIa mediated arterial thrombosis platelet activation plays a central role. To discover platelet activation inhibitor the pharmacophores of GPIIb/IIIa receptor inhibitors and anti-thrombotic agents were analyzed. This led to the design of (1R,3S)- and (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acids as GPIIb/IIIa inhibitors. Comparing to (1S,3S)-isomer (1R,3S)-isomer had lower cdocker interaction energy. AFM image showed that the minimal effective concentration of (1S,3S)-isomer and (1R,3S)-isomer inhibiting platelet activation were 10−5M and 10−6M, respectively.In vivo1 μmol/kg of oral (1S,3S)-isomer effectively inhibited the rats to form arterial thrombus and down regulated GPIIb/IIIa expression, but the activities were significantly lower than those of 1 μmol/kg of oral (1R,3S)-isomer. Both (1S,3S)-isomer and (1R,3S)-isomer can be safely used for structural modifications, but (1R,3S)-isomer should be superior to (1S,3S)-isomer.