Structure and location of amiodarone in a membrane bilayer as determined by molecular mechanics and quantitative x-ray diffraction.
Structure and location of amiodarone in a membrane bilayer as determined by molecular mechanics and quantitative x-ray diffraction.
复制标题
通过分子力学和定量 X 射线衍射确定胺碘酮在膜双层中的结构和位置。
DOI：
10.1016/s0006-3495(88)82986-2
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发表时间：
1988
影响因子：
3.4
通讯作者：
Herbette,LG
中科院分区：
文献类型：
--
作者：
Trumbore,M;Chester,DW;Moring,J;Rhodes,D;Herbette,LG
胺碘酮是一种用于治疗心律失常的药物，被认为与细胞膜具有持久的相互作用。本研究旨在检查胺碘酮在膜双层中的结构和位置。胺碘酮具有约10（6）的高膜分配系数。采用小角X射线衍射法测定了二棕榈酰磷脂酰胆碱（DPPC）脂质双层中胺碘酮碘原子在低温和水合条件下的位置，其中DPPC双层处于凝胶状态。碘原子的时间平均位置被确定为距离脂质双层的中心（末端甲基区域）约6 A。在计算膜结合胺碘酮的最小能量结构时，使用了介电常数kappa=2（接近双层烃核心区域的介电常数）。与胺碘酮的晶体结构相比，该计算结构表明胺碘酮在双层中的构象与晶体中的构象显著不同。这里报道的结果是一种尝试，其时间平均构象的脂质双层中的膜活性药物的位置相关联。这种类型的分析有望在设计具有更大效力和更高特异性的药物方面发挥重要作用。
Amiodarone is a drug used in the treatment of cardiac arrhythmias and is believed to have a persistent interaction with cellular membranes. This study sought to examine the structure and location of amiodarone in a membrane bilayer. Amiodarone has a high membrane partition coefficient on the order of 10(6). Small angle x-ray diffraction was used to determine the position of the iodine atoms of amiodarone in dipalmitoylphosphatidylcholine (DPPC) lipid bilayers under conditions of low temperature and hydration where the DPPC bilayer is in the gel state. The time-averaged position of the iodine atoms was determined to be approximately 6 A from the center (terminal methyl region) of the lipid bilayer. A dielectric constant of kappa=2, which approximates that of the bilayer hydrocarbon core region, was used in calculating a minimum energy structure for membrane-bound amiodarone. This calculated structure when compared with the crystal structure of amiodarone demonstrated that amiodarone could assume a conformation in the bilayer significantly different from that in the crystal. The results reported here are an attempt to correlate the position of a membrane-active drug in a lipid bilayer with its time-averaged conformation. This type of analysis promises to be of great use in the design of drugs with greater potency and higher specificity.