Molecular docking study of the binding of aminopyridines within the K+ channel
Molecular docking study of the binding of aminopyridines within the K+ channel
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DOI：
10.1007/s00894-007-0184-9
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发表时间：
2007-05-01
影响因子：
2.2
通讯作者：
Munoz-Caro, Camelia
中科院分区：
文献类型：
--
作者：
Caballero, Norma Angelica;Melendez, Francisco Javier;Munoz-Caro, Camelia
我们提出了一个分子对接研究，旨在确定质子化氨基吡啶的电压依赖性钾通道的阻断结合位点。考虑了几种活性氨基吡啶：2-氨基吡啶、3-氨基吡啶、4-氨基吡啶、3，4-二氨基吡啶和4-氨基喹啉。我们应用AutoDock力场与拉马克遗传算法，使用来自在B3 LYP/cc-pVDZ水平上获得的静电势的配体的原子电荷。我们发现一个区域的α-亚基的K+通道轴承共同的结合位点。该区域对应于KcsA K+通道（1 J 95 PDB结构）中残基Thr 107和Ala 111之间包含的5个氨基酸。2-氨基吡啶、3-氨基吡啶、4-氨基吡啶和3，4-二氨基吡啶与Thr 107和Ala 111的羧基氧结合。在所有情况下，氨基吡啶都垂直于孔的轴。4-氨基喹啉与Ala 111的羧基氧结合。由于其大尺寸，分子平面平行于孔的轴。结合复合物的电荷分布和结构表明，相互作用是由几个氢键的形成。我们发现2-氨基吡啶、3-氨基吡啶、4-氨基吡啶和3，4-二氨基吡啶具有相似的结合能。考虑到AutoDock力场估计值的标准误差，作为粗略估计，该能量应在3-7 kcal mol（-1）区间内。另一方面，4-氨基喹啉似乎具有较小的结合能。
We present a molecular docking study aimed to identify the binding site of protonated aminopyridines for the blocking of voltage dependent K+ channels. Several active aminopyridines are considered: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. We apply the AutoDock force field with a lamarckian genetic algorithm, using atomic charges for the ligands derived from the electrostatic potential obtained at the B3LYP/cc-pVDZ level. We find a zone in the alpha-subunit of the K+ channel bearing common binding sites. This zone corresponds to five amino acids comprised between residuals Thr107 and Ala111, in the KcsA K+ channel (1J95 pdb structure). The 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine bind to the carboxylic oxygens of Thr107 and Ala111. In all cases aminopyridines are perpendicular to the axis of the pore. 4-aminoquinoleine binds to the carboxylic oxygen of Ala111. Due to its large size, the molecular plane is parallel to the axis of the pore. The charge distributions and the structures of the binding complexes suggest that the interaction is driven by formation of several hydrogen bonds. We find 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine with similar binding energy. Considering the standard error of the estimate of the AutoDock force field, this energy should lie, as a rough estimation, in the interval 3-7 kcal mol(-1). On the other hand, 4-aminoquinoleine seems to have a smaller binding energy.