分子模拟的卡马西平和烟碱受体的相互作用参与常染色体显性遗传夜间额叶癫痫。

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Ortells MO, Barrantes通用电气

分子模拟的卡马西平和烟碱受体的相互作用参与常染色体显性遗传夜间额叶癫痫。

Br J杂志。2002年7月,136 (6):883 - 95。doi: 10.1038 / sj.bjp.0704786。

PubMed ID

12110613 (在PubMed

]

文摘

1。正常和突变(S248F)人类神经元alpha4beta2烟碱受体起作用,及其与通道阻滞剂卡马西平(卡马西平)的交互模型。突变体,负责常染色体显性遗传夜间额叶癫痫(ADNFLE),有增强灵敏度和较慢的复苏从脱敏,较低的电导,短暂开放时间,减少钙渗透率,卡马西平,3折更敏感,一种药物用于治疗部分癫痫病。2。突变通道属性是解释两个Phe248侧链的物理化学性质,包括大小和cation-pi互动,和他们的动态行为。有缺陷的脱水机理可能是负责减少钙流入。3所示。Phe248残留的主要成分是卡马西平结合位点突变,虽然这不是真正的Ser248正常的受体。4所示。更多的阻塞结合位点和预测更高的亲和力发现卡马西平的变异占其微分对卡马西平的敏感性。 5. Aromatic-aromatic interactions between CBZ and the two Phe248 account for the difference in affinity, which is at least 12 times higher for the mutant, depending on the method used for calculating K(i). 6. Normal vs mutant differences in K(i), enhanced by the higher number of blocking binding sites in the mutant, seem excessive compared to the differential sensitivities to CBZ experimentally found. The negative cooperativity suggested by a predicted overlapping of blocking and non-blocking binding sites gives an explanation, as overlapping is higher in the mutant. 7. For both types of receptors we found that the carbamyl group of the best blocking conformers of CBZ forms hydrogen bonds with serine residues, which may explain the fundamental role of that moiety for this molecule to act as antiepileptic drug.

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药物靶点

药物	目标	类	生物	药理作用	行动
卡马西平	神经乙酰胆碱受体亚基alpha 4	蛋白质	人类	未知的	不可用	细节