伊芬普地尔
变构调节
NMDA受体
药效团
生物
受体
谷氨酸受体
突变
生物信息学
结合位点
对接(动物)
神经科学
药理学
化学
计算生物学
生物化学
突变体
医学
基因
护理部
作者
David Stroebel,Derek L. Buhl,John D. Knafels,Pranab K. Chanda,Michael F. Green,Simone Sciabola,Laetitia Mony,Pierre Paoletti,Jayvardhan Pandit
出处
期刊:Molecular Pharmacology
[American Society for Pharmacology & Experimental Therapeutics]
日期:2016-02-24
卷期号:89 (5): 541-551
被引量:68
标识
DOI:10.1124/mol.115.103036
摘要
N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that play key roles in brain physiology and pathology. Because numerous pathologic conditions involve NMDAR overactivation, subunit-selective antagonists hold strong therapeutic potential, although clinical successes remain limited. Among the most promising NMDAR-targeting drugs are allosteric inhibitors of GluN2B-containing receptors. Since the discovery of ifenprodil, a range of GluN2B-selective compounds with strikingly different structural motifs have been identified. This molecular diversity raises the possibility of distinct binding sites, although supporting data are lacking. Using X-ray crystallography, we show that EVT-101, a GluN2B antagonist structurally unrelated to the classic phenylethanolamine pharmacophore, binds at the same GluN1/GluN2B dimer interface as ifenprodil but adopts a remarkably different binding mode involving a distinct subcavity and receptor interactions. Mutagenesis experiments demonstrate that this novel binding site is physiologically relevant. Moreover, in silico docking unveils that GluN2B-selective antagonists broadly divide into two distinct classes according to binding pose. These data widen the allosteric and pharmacological landscape of NMDARs and offer a renewed structural framework for designing next-generation GluN2B antagonists with therapeutic value for brain disorders.
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