Suppr超能文献

芳香环在氨基糖苷类抗生素分子识别中的作用:对药物设计的启示。

Role of aromatic rings in the molecular recognition of aminoglycoside antibiotics: implications for drug design.

机构信息

Instituto de Química Orgánica General (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.

出版信息

J Am Chem Soc. 2010 Sep 1;132(34):12074-90. doi: 10.1021/ja1046439.

Abstract

Aminoglycoside antibiotics participate in a large variety of binding processes involving both RNA and proteins. The description, in recent years, of several clinically relevant aminoglycoside/receptor complexes has greatly stimulated the structural-based design of new bioactive derivatives. Unfortunately, design efforts have frequently met with limited success, reflecting our incomplete understanding of the molecular determinants for the antibiotic recognition. Intriguingly, aromatic rings of the protein/RNA receptors seem to be key actors in this process. Indeed, close inspection of the structural information available reveals that they are frequently involved in CH/pi stacking interactions with sugar/aminocyclitol rings of the antibiotic. While the interaction between neutral carbohydrates and aromatic rings has been studied in detail during past decade, little is known about these contacts when they involve densely charged glycosides. Herein we report a detailed experimental and theoretical analysis of the role played by CH/pi stacking interactions in the molecular recognition of aminoglycosides. Our study aims to determine the influence that the antibiotic polycationic character has on the stability, preferred geometry, and dynamics of these particular contacts. With this purpose, different aminoglycoside/aromatic complexes have been selected as model systems. They varied from simple bimolecular interactions to the more stable intramolecular CH/pi contacts present in designed derivatives. The obtained results highlight the key role played by electrostatic forces and the desolvation of charged groups in the molecular recognition of polycationic glycosides and have clear implications for the design of improved antibiotics.

摘要

氨基糖苷类抗生素参与涉及 RNA 和蛋白质的多种结合过程。近年来,描述了几种临床相关的氨基糖苷/受体复合物,极大地激发了新型生物活性衍生物的基于结构的设计。不幸的是,设计工作经常遇到有限的成功,这反映了我们对抗生素识别的分子决定因素的不完全理解。有趣的是,蛋白质/RNA 受体的芳环似乎是这个过程的关键因素。事实上,仔细检查现有的结构信息表明,它们经常与抗生素的糖/氨基环醇环发生 CH/pi 堆积相互作用。虽然过去十年中已经详细研究了中性碳水化合物与芳环之间的相互作用,但当涉及到带密集电荷的糖苷时,这些相互作用知之甚少。本文报道了 CH/pi 堆积相互作用在氨基糖苷类分子识别中所起作用的详细实验和理论分析。我们的研究旨在确定抗生素多电荷特性对这些特殊接触的稳定性、优选几何形状和动力学的影响。为此,选择了不同的氨基糖苷/芳环复合物作为模型系统。它们从简单的双分子相互作用到设计衍生物中存在的更稳定的分子内 CH/pi 接触。所得结果突出了静电相互作用力和带电基团去溶剂化在多阳离子糖苷分子识别中的关键作用,并对设计改进的抗生素具有明确的意义。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验