Extraction and Analysis of Chemical Modification Patterns in Drug Development
Extraction and Analysis of Chemical Modification Patterns in Drug Development
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DOI：
10.1021/ci8003804
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发表时间：
2009-04-01
影响因子：
5.6
通讯作者：
Kanehisa, Minoru
中科院分区：
文献类型：
--
作者：
Shigemizu, Daichi;Araki, Michihiro;Kanehisa, Minoru
在药物开发过程中，大多数药物都是由原型化合物不断进行修饰的。这种药物发展史上的化学修饰被认为包含了丰富的药物化学家的知识，而KEGG药物结构图的编制就是为了捕捉这些知识。在这里，我们试图从KEGG DRUG数据库中的3745种已批准的药物和KEGG DRUG结构图中的255种药物对中提取化学修饰模式信息。我们首先利用位表示指纹和相似结构的分层聚类从KEGG DRUG数据库中鉴定出236个核心结构和506个外围片段。然后，我们研究了核心结构和外围片段之间的位置依赖关系，揭示了特定片段与核心结构上特定修饰位点连接的趋势。接下来，我们在修饰位点将药物对转化为204个外周片段变化。每个变化都用指纹比特模式差异的变换轮廓来表示，并对相似的变换轮廓进行分层聚类。因此，我们确定了125种化学修饰模式，这些模式表征了KEGG药物结构图。这些模式进一步应用于新的结构图的重建。本文提出的方法可能适用于系统的硅药物修饰。
Most drugs have been continuously modified from prototypic compounds in the drug development process. Such chemical modifications in the history of drug development are expected to contain a wealth of medicinal chemists' knowledge, and the KEGG DRUG structure maps have been compiled to capture this knowledge. Here we attempted to extract the information on the chemical modification patterns from 3745 approved drugs in the KEGG DRUG database and 255 drug pairs in the KEGG DRUG structure maps. We first identified 236 core structures and 506 peripheral fragments from the KEGG DRUG database using bit-represented fingerprints and hierarchical clustering of similar structures. We then examined position-dependent relationships between core structures and peripheral fragments, which revealed the tendency of specific fragments connected to specific modification sites on the core structures. Next we converted the drug pairs into 204 peripheral fragment changes at the modification sites. Each change was represented by the transformation profile defined as a difference of fingerprint bit patterns, and the hierarchical clustering of similar transformation profiles was performed. We thus identified 125 chemical modification patterns that characterize the KEGG DRUG structure maps. These patterns were further applied to the reconstruction of a new structure map. The approach presented here may be applicable to systematic in silico drug modifications.