Search for novel aminoglycosides by combining fragment-based virtual screening and 3D-QSAR scoring.
Search for novel aminoglycosides by combining fragment-based virtual screening and 3D-QSAR scoring.
复制标题
通过结合基于片段的虚拟筛选和 3D-QSAR 评分来搜索新型氨基糖苷类药物。
DOI：
10.1021/ci800361a
复制
发表时间：
2009
影响因子：
5.6
通讯作者：
Trylska,Joanna
中科院分区：
文献类型：
--
作者：
Setny,Piotr;Trylska,Joanna
氨基糖苷类是一种靶向细菌核糖体16S RNA A位点的抗生素。已经有许多努力直接设计其合成衍生物，但只有少数成功。作为RNA结合物，氨基糖苷也是计算药物设计的一个困难目标，因为大多数现有方法都是针对蛋白质配体开发的。在这里，我们提出了一种方法，可以避免与仍然欠发达的RNA对接和评分算法相关的问题。目的是鉴定可能与A位点结合的新分子支架。考虑的分子是基于邻胺核的，邻胺核对所有氨基糖苷都是常见的，并且提供了对结合位点的特异性，通过其O5或O6氧原子与不同的分子片段连接。利用基于氨基糖苷- rna复合物结构数据设计的两种不同的药效团，对分子片段库进行3D搜索，选择合适的片段。然后，利用已知氨基糖苷衍生物的生物学数据开发的3D-QSAR模型对与邻胺组装的片段产生的化合物进行评分。获得了21种新的潜在配体，其中4种预测活性可与效力较弱的氨基糖苷类抗生素相媲美。
Aminoglycosides are antibiotics targeting the 16S RNA A site of the bacterial ribosome. There have been many efforts directed toward design of their synthetic derivatives, however with only few successes. As RNA binders, aminoglycosides are also a difficult target for computational drug design, since most of the existing methods were developed for protein ligands. Here, we present an approach that allows for evading the problems related to still poorly developed RNA docking and scoring algorithms. It is aimed at identification of new molecular scaffolds potentially binding to the A site. The considered molecules are based on the neamine core, which is common for all aminoglycosides and provides specificity toward the binding site, linked with diverse molecular fragments via its O5 or O6 oxygen atom. Suitable fragments are selected with the use of 3D searches of molecular fragments library against two distinct pharmacophores designed on the basis of available structural data for aminoglycoside-RNA complexes. The compounds resulting from fragments assembly with neamine are then scored with a 3D-QSAR model developed using the biological data for known aminoglycoside derivatives. Twenty-one new potential ligands are obtained, four of which have predicted activities comparable to less potent aminoglycoside antibiotics.