Disrupting the interaction between the PDZ protein, PSD-95, and its target ligands (such as the glutamate NMDA receptor or the serotonin 5-HT2A receptor) was found to reduce hyperalgesia in various models of neuropathic pain. Here, we set out to identify lead molecules which would interact with PSD-95, and hence, would potentially display analgesic activity. We describe the virtual screening of the Asinex and Cambridge databases which together contain almost one million molecules. Using three successive docking filters and visual inspection, we identified three structural classes of molecules and synthesized a potential lead compound from each class. The binding of the molecules with the PDZ domains of PSD-95 was assessed by (1)H-(15)N HSQC NMR experiments. The analgesic activity of the best ligand, quinoline 2, was evaluated in vivo in a model of neuropathic pain and showed promising results.

译文

:在各种神经性疼痛模型中,发现破坏PDZ蛋白,PSD-95及其靶配体(例如谷氨酸NMDA受体或血清素5-HT2A受体)之间的相互作用可减少痛觉过敏。在这里,我们着手确定将与PSD-95相互作用的铅分子,从而潜在地显示出止痛活性。我们描述了一起包含近一百万个分子的Asinex和Cambridge数据库的虚拟筛选。使用三个连续的对接过滤器和目视检查,我们确定了分子的三个结构类别,并从每个类别中合成了潜在的先导化合物。通过(1)H-(15)N HSQC NMR实验评估了分子与PSD-95的PDZ域的结合。最佳配体喹啉2的镇痛活性已在神经性疼痛模型中进行了体内评估,并显示出令人鼓舞的结果。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录