Langs D A, Strong P D, Triggle D J
Department of Molecular Biophysics, Medical Foundation of Buffalo, Inc., NY 14203.
J Comput Aided Mol Des. 1990 Sep;4(3):215-30. doi: 10.1007/BF00125011.
Our analysis of the solid state conformations of nifedipine [dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate ] and its 1,4-dihydropyridine (1,4-DHP) analogues produced a cartoon description of the important interactions between these drugs and their voltage-dependent calcium channel receptor. In the present study a molecular-level detailed model of the 1,4-DHP receptor binding site has been built from the published amino acid sequence of the alpha 1 subunit of the voltage-dependent calcium channel isolated from rabbit skeletal muscle transverse tubule membranes. The voltage-sensing component of the channel described in this work differs from other reported for the homologous sodium channel in that it incorporates a water structure and a staggered, rather than eclipsed, hydrogen bonded S4 helix conformation. The major recognition surfaces of the receptor lie in helical grooves on the S4 or voltage-sensing alpha-helix that is positioned in the center of the bundle of transmembrane helices that define each of the four calcium channel domains. Multiple binding clefts defined by Arg-X-X-Arg-P-X-X-S 'reading frames' exist on the S4 strand. The tissue selectivity of nifedipine and its analogues may arise, in part, from conservative changes in the amino acid residues at the P and S positions of the reading frame that define the ester-binding regions of receptors from different tissues. The crystal structures of two tissue-selective nifedipine analogues, nimodipine [isopropyl (2-methoxyethyl) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate ] and nitrendipine [ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinecarboxylate] are reported. Nimodipine was observed to have an unusual ester side chain conformation that enhances the fit to the proposed ester-sensing region of the receptor.
我们对硝苯地平[1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二甲酸二甲酯]及其1,4-二氢吡啶（1,4-DHP）类似物的固态构象分析，得出了这些药物与其电压依赖性钙通道受体之间重要相互作用的直观描述。在本研究中，已根据从兔骨骼肌横管膜分离出的电压依赖性钙通道α1亚基的已发表氨基酸序列，构建了1,4-DHP受体结合位点的分子水平详细模型。本文所述通道的电压传感组件与报道的同源钠通道不同，因为它包含一个水结构以及一个交错而非重叠的氢键连接的S4螺旋构象。受体的主要识别表面位于S4或电压传感α螺旋上的螺旋凹槽中，该螺旋位于定义四个钙通道结构域中每一个的跨膜螺旋束的中心。S4链上存在由Arg-X-X-Arg-P-X-X-S“阅读框”定义的多个结合裂隙。硝苯地平及其类似物的组织选择性可能部分源于定义不同组织受体酯结合区域的阅读框中P和S位置氨基酸残基的保守变化。报道了两种组织选择性硝苯地平类似物尼莫地平[1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二甲酸(2-甲氧基乙基)异丙酯]和尼群地平[1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二甲酸甲乙酯]的晶体结构。观察到尼莫地平具有不寻常的酯侧链构象，增强了与受体拟议酯传感区域的契合度。
