Docking of cationic antibiotics to negatively charged pockets in RNA folds
Docking of cationic antibiotics to negatively charged pockets in RNA folds
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DOI：
10.1021/jm981108g
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发表时间：
1999-04-08
影响因子：
7.3
通讯作者：
Westhof, E
中科院分区：
文献类型：
--
作者：
Hermann, T;Westhof, E
氨基糖苷与RNA的结合为RNA-药物相互作用的分析提供了一个范例系统。三维RNA折叠周围的静电场产生了局部和确定的带负电荷的区域，这些区域是氨基糖苷的阳离子铵基的潜在对接位点。为了探索RNA折叠中适合氨基糖苷结合的电负性口袋，我们使用了静电场计算和阳离子扩散的布朗动力学模拟。我们将这项技术应用于那些实验上已知能结合氨基糖苷的RNA分子，即两种妥布霉素适体（Wang， Y.; Rando,:R.）。r .化学。人类免疫缺陷病毒（human immunodeficiency virus, nhiv, 1987, 327, 389-394）中的氨基糖苷结合区（amindglycoside binding region） （ei, h - y .; et al.）。Bioorg。地中海,化学。Lett. 1995, 5, 2755-2760)。对于已知氨基糖苷结合位点的适体和核糖体RNA，发现带负电荷的口袋与药物的结合位置之间有很好的一致性。基于新霉素类和卡那霉素类氨基糖苷类与核糖体RNA静电场相互作用的差异，我们提出了这两类药物不同结合特异性的模型。利用RNA折叠中电负性口袋与氨基糖苷结合位置之间的空间一致性，将氨基糖苷与核糖体和TAR RNA对接。分子动力学模拟用于分析可能的rna -药物相互作用。氨基糖苷抑制病毒Tat蛋白与TAR RNA的结合；然而，药物结合位点仍然未知。因此，我们的对接方法提供了tar -氨基糖苷复合物的第一个结构模型。在模拟复合物中观察到的rna -药物相互作用支持了抗生素可能将TAR锁定在对Tat蛋白具有低亲和力的构象中的观点，这解释了实验中发现的氨基糖苷抑制Tat-TAR相互作用的现象（Mei， H.-Y.; et al.）。Bioorg。地中海,化学。Lett. 1995, 5, 2755-2760)。
The binding of aminoglycosides to RNA provides a paradigm system for the analysis of RNA-drug interactions. The electrostatic field around three-dimensional RNA folds creates localized and defined negatively charged regions which are potential docking sites for the cationic ammonium groups of aminoglycosides. To explore in RNA folds the electronegative pockets suitable for aminoglycoside binding, we used calculations of the electrostatic field and Brownian dynamics simulations of cation diffusion. We-applied the technique on those RNA molecules experimentally known to bind aminoglycosides, namely, two tobramycin aptamers (Wang, Y.; Rando,:R. R. Chem. Biol. 1995, 2, 281-290): the amindglycoside-binding region in 16S ribosomal RNA (Moazed, S.; Noller, H. F. Nature 1987, 327, 389-394) and the TAR RNA from human immunodeficiency virus (Mei, H.-Y.; et al. Bioorg. Med. Chem. Lett. 1995, 5, 2755-2760). For the aptamers and ribosomal RNA, for which the binding sites of the aminoglycosides are known, a good agreement between negatively charged pockets and the binding positions of the drugs was found. On the basis of variations between neomycin-like and kanamycin-like aminoglycosides in the interaction with the electrostatic field of ribosomal RNA, we propose a model for the different binding specificities of these two classes of drugs. The spatial congruence between the electronegative pockets in RNA folds and binding positions of aminoglycosides was used to dock aminoglycosides to ribosomal and TAR RNAs. Molecular dynamics simulations were used to analyze possible RNA-drug interactions. Aminoglycosides inhibit the binding of the viral Tat protein to TAR RNA; however, the drug-binding sites are still unknown. Thus, our docking approach provides first structural models for TAR-aminoglycoside complexes. The RNA-drug interactions observed in the modeled complexes support the view that the antibiotics might lock TAR in a conformation with low affinity for the Tat protein, explaining the experimentally found aminoglycoside inhibition of the Tat-TAR interaction (Mei, H.-Y.; et al. Bioorg. Med. Chem. Lett. 1995, 5, 2755-2760).