Structure-based drug design meets the ribosome
Structure-based drug design meets the ribosome
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DOI：
10.1016/j.bcp.2005.12.026
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发表时间：
2006-03-30
影响因子：
5.8
通讯作者：
Duffy, EM
中科院分区：
文献类型：
--
作者：
Franceschi, F;Duffy, EM
细菌核糖体亚基及其与抗生素复合物的高分辨率结构极大地促进了我们对小分子与 RNA 相互作用的理解。这些结构生成的大量 RNA 结构数据使计算化学家能够采用专注于基于 RNA 的靶标的药物发现范式。这些结构还显示了基于靶标的耐药性如何影响在核糖体水平上发挥作用的抗生素。不仅精确定位了不同类别抗生素抑制蛋白质合成的位点，而且还在原子水平上揭示了它们的方向、相对配置和独特的作用机制。 30S 和 50S 核糖体亚基均已被证明是“靶标的靶标”，为抗生素提供了几个相邻的、功能相关的结合袋。正是对这些经过验证的位置或核糖功能位点的详细了解，加上耐药热点的映射，才可以合理设计下一代抗菌药物。当结构信息与能够描述和预测适合细菌细胞渗透和药物相似性的分子特性的数据驱动计算工具包相结合时，基于结构的新型抗菌药物设计方法显示出巨大的前景。 (c) 2006 Elsevier Inc. 保留所有权利。
The high-resolution structures of the bacterial ribosomal subunits and those of their complexes with antibiotics have advanced significantly our understanding of small-molecule interactions with RNA. The wealth of RNA structural data generated by these structures has allowed computational chemists to employ a drug discovery paradigm focused on RNA-based targets. The structures also show how target-based resistance affects antibiotics acting at the level of the ribosome. Not only are the sites pinpointed where different classes of antibiotics inhibit protein synthesis, but their orientations, relative dispositions, and unique mechanisms of action are also revealed at the atomic level. Both the 30S and the 50S ribosomal subunits have been shown to be "targets of targets", offering several adjacent, functionally relevant binding pockets for antibiotics. It is the detailed knowledge of these validated locations, or ribofunctional loci, plus the mapping of the resistance hot-spots that allow the rational design of next-generation antibacterials.When the structural information is combined with a data-driven computational toolkit able to describe and predict molecular properties appropriate for bacterial cell penetration and drug-likeness, a structure-based drug design approach for novel antibacterials shows great promise. (c) 2006 Elsevier Inc. All rights reserved.