Aquaporin Inhibition by Gold(III) Compounds: New Insights
Aquaporin Inhibition by Gold(III) Compounds: New Insights
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DOI：
10.1002/cmdc.201300107
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发表时间：
2013-07-01
期刊：
影响因子：
3.4
通讯作者：
Casini, Angela
中科院分区：
文献类型：
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作者：
Martins, Ana Paula;Ciancetta, Antonella;Casini, Angela
水通道蛋白(Aquaporins，AQP)是一种膜上的水/甘油通道，在生物系统中具有重要作用，也是治疗和成像的潜在靶点。用停流法研究了1，10-菲托林、2，2-联吡啶、4，4-二甲基-2，2-联吡啶、4，4-二氨基-2，2-联吡啶和2，2；2-三联吡啶等一系列含氮配体的金(III)、铂(II)和铜(II)配合物在表达水和甘油运动的人红细胞中的作用。结果表明，金(III)络合物选择性地通过AQP1对AQP3进行调节。随后进行了分子模拟和密度泛函理论(DFT)计算，以使观察结果合理化，并研究了这些金化合物作用于其假定目标(AQP3)的可能分子机制。在没有任何结晶学数据的情况下，使用以前报道的同源模型来实现这一目的。综上所述，本研究的结果表明，对这些溶质通道的有效和选择性的调节是可能的，但这类药物对所有AQP亚型的选择性及其潜在的治疗用途还需要进一步的研究。
Aquaporins (AQPs) are membrane water/glycerol channels with essential roles in biological systems, as well as being promising targets for therapy and imaging. Using a stopped-flow method, a series of gold(III), platinum(II) and copper(II) complexes bearing nitrogen donor ligands, such as 1,10-phenatroline, 2,2-bipyridine, 4,4-dimethyl-2,2-bipyridine, 4,4-diamino-2,2-bipyridine and 2,2;6,2-terpyridine, were evaluated in human red blood cells expressing AQP1 and AQP3, responsible for water and glycerol movement, respectively. The results showed that the gold(III) complexes selectively modulate AQP3 over AQP1. Molecular modeling and density functional theory (DFT) calculations were subsequently performed to rationalize the observations and to investigate the possible molecular mechanism through which these gold compounds act on their putative target (AQP3). In the absence of any crystallographic data, a previously reported homology model was used for this purpose. Combined, the findings of this study show that potent and selective modulation of these solute channels is possible, however further investigation is required into the selectivity of this class of agents against all AQP isoforms and their potential therapeutic uses.