Characterization of the Chemical Space of Known and Readily Obtainable Natural Products
Characterization of the Chemical Space of Known and Readily Obtainable Natural Products
复制标题
DOI：
10.1021/acs.jcim.8b00302
复制
发表时间：
2018-08-01
影响因子：
5.6
通讯作者：
Kirchmair, Johannes
中科院分区：
文献类型：
--
作者：
Chen, Ya;de Lomana, Marina Garcia;Kirchmair, Johannes
天然产物仍然是开发新药的最有生产力的化学灵感来源之一。公共数据库中有超过25万种天然产物的结构。这些化合物中至少有10%很容易从商业供应商和公共研究机构获得实验测试。虽然已知天然产物的物理化学性质已经得到了彻底的研究，并与药物和其他类型的小分子进行了比较，但关于单个虚拟和物理天然产物库的内容、覆盖范围和相关性的可用信息显然是有限的。这项研究的目的是通过已知的和容易获得的天然产物和单个天然产物数据库来详细了解化学空间的覆盖范围。为此，我们从18个虚拟数据库（包括天然产物词典）、9个物理库和蛋白质数据库（PDB）中编译了已知和容易获得的天然产物的综合数据集。我们还开发并采用了一种算法（“SugarBuster”），用于从天然产物中去除糖和类糖部分，这些部分通常不是药物发现的重点。此外，我们还设计了一种基于规则的方法，将天然产物自动分类为天然产物类别（生物碱、类固醇、类黄酮等）。本研究最重要的结果之一是发现容易获得的天然产物是高度多样化的，并且分布在与药物发现高度相关的化学空间区域。在某些情况下，观察到各个数据库对天然产品类别和化学空间的覆盖范围存在很大差异。超过2000种天然产物被确定，其中至少有一种与生物大分子复合物的x射线晶体结构可从PDB中获得。
Natural products remain one of the most productive sources of chemical inspiration for the development of new drugs. The structures of more than 250 000 natural products are available from public databases. At least 10% of these compounds are readily obtainable for experimental testing from commercial vendors and public research institutions. While the physicochemical properties of known natural products have been thoroughly studied and compared to those of drugs and other types of small molecules, the information available on the content, coverage, and relevance of individual virtual and physical natural product libraries is clearly limited. The aim of this study was the development of a detailed understanding of the coverage of chemical space by known and readily obtainable natural products and by individual natural product databases. For this purpose, we compiled comprehensive data sets of known and readily obtainable natural products from 18 virtual databases (including the Dictionary of Natural Products), nine physical libraries, and the Protein Data Bank (PDB). We also developed and employed an algorithm ("SugarBuster") for the removal of sugars and sugar-like moieties, which are generally not in the focus of interest for drug discovery, from natural products. In addition, we devised a rule-based approach for the automated classification of natural products into natural product classes (alkaloids, steroids, flavonoids, etc.). Among the most important results of this study is the finding that the readily obtainable natural products are highly diverse and populate regions of chemical space that are of high relevance to drug discovery. In some cases, substantial differences in the coverage of natural product classes and chemical space by the individual databases are observed. More than 2000 natural products are identified for which at least one X-ray crystal structure of the compound in complex with a biomacromolecule is available from the PDB.