Gitto Rosaria, De Luca Laura, Ferro Stefania, Occhiuto Francesco, Samperi Stefania, De Sarro Giovanbattista, Russo Emilio, Ciranna Lucia, Costa Lara, Chimirri Alba
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università di Messina, Viale Annunziata, 98168 Messina, Italy.
ChemMedChem. 2008 Oct;3(10):1539-48. doi: 10.1002/cmdc.200800124.
The ionotropic glutamate NMDA/NR2B receptor and its interaction with ifenprodil-like noncompetitive ligands were investigated by a combined ligand-based and target-based approach. First, we generated 3D pharmacophore hypotheses and identified common chemical features that are shared by a training set of well-known NR2B antagonists. The binding mode of the most representative ligand was also studied by molecular docking. Because the docking results and the suggested 3D pharmacophore model were in good agreement, we obtained new information about the NR2B ifenprodil site. The best pharmacophoric hypothesis was used as a query for in silico screening; this allowed the identification of new "hit". We synthesized "hit-compound" analogues, and some of the molecules showed significant activity both in binding and functional assay as well as in vivo anticonvulsant efficacy in DBA/2 mice. The most active derivatives also exhibited neuroprotective effects against glutamate-induced toxicity in HCN-1A cells.
采用基于配体和基于靶点的联合方法，对离子型谷氨酸NMDA/NR2B受体及其与艾芬地尔样非竞争性配体的相互作用进行了研究。首先，我们生成了三维药效团假设，并确定了一组著名的NR2B拮抗剂训练集共有的常见化学特征。还通过分子对接研究了最具代表性配体的结合模式。由于对接结果与所提出的三维药效团模型高度吻合，我们获得了有关NR2B艾芬地尔位点的新信息。最佳药效团假设被用作计算机模拟筛选的查询条件；这使得能够识别新的“命中物”。我们合成了“命中化合物”类似物，其中一些分子在结合和功能测定中均显示出显著活性，并且在DBA/2小鼠中具有体内抗惊厥功效。活性最高的衍生物还对HCN-1A细胞中谷氨酸诱导的毒性表现出神经保护作用。
