Extending the Activity Cliff Concept: Structural Categorization of Activity Cliffs and Systematic Identification of Different Types of Cliffs in the ChEMBL Database
Extending the Activity Cliff Concept: Structural Categorization of Activity Cliffs and Systematic Identification of Different Types of Cliffs in the ChEMBL Database
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DOI：
10.1021/ci300274c
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发表时间：
2012-07-01
影响因子：
5.6
通讯作者：
Bajorath, Juergen
中科院分区：
文献类型：
--
作者：
Hu, Ye;Bajorath, Juergen
活性悬崖通常被理解为效价差异较大的相似化合物对或组。鉴于悬崖的“小化学变化-大效力效应”表型，活动悬崖的研究对于复合数据集活动景观的表征和 SAR 决定因素的识别具有很高的意义。在这里，我们介绍了一种新的活动悬崖结构分类方案，并介绍了新的悬崖类型。活性悬崖分为五个不同的类别，具体取决于参与的化合物是否仅通过手性、拓扑、R 基团集、核心结构（支架）或核心结构和 R 基团拓扑来区分。所有悬崖类型都经常在 ChEMBL 数据库中检测到。正如人们所预料的那样，R 组悬崖比其他悬崖类型出现的可能性更高。然而，许多支架和 R 基悬崖并不是基于全分子相似性计算来识别的，尽管它们通常在化学上是直观的。这使得活性悬崖分类对于药物化学分析具有吸引力，与相似性计算无关。基于明确定义的结构标准的活动悬崖分配补充并进一步扩展了当前识别和表示悬崖的方法。
Activity cliffs are generally understood as pairs or groups of similar compounds with large differences in potency. The study of activity cliffs is of high interest for the characterization of activity landscapes of compound data sets and the identification of SAR determinants, given the "small chemical change(s)-large potency effect" phenotype of cliffs. Herein, we introduce a new structural classification scheme for activity cliffs and introduce new cliff types. Activity cliffs are divided into five different classes dependent on whether the participating compounds are only distinguished by chirality, topology, R-group sets, core structures (scaffolds), or core structures and R-group topology. All cliff types are frequently detected in the ChEMBL database. R-group cliffs occur with higher propensity than other cliff types, as one might expect. However, many scaffold and R-group cliffs are not identified on the basis of whole-molecule similarity calculations, although they are often chemically intuitive. This makes the activity cliff classification attractive for medicinal chemistry analysis, independent of similarity calculations. Assignment of activity cliffs on the basis of well-defined structural criteria complements and further extends current approaches to identify and represent cliffs.