Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität , Dahlmannstr. 2, D-53113 Bonn, Germany.
J Chem Inf Model. 2014 Feb 24;54(2):451-61. doi: 10.1021/ci400728r. Epub 2014 Jan 30.
The assessment of activity cliffs has thus far mostly focused on compound pairs, although the majority of activity cliffs are not formed in isolation but in a coordinated manner involving multiple active compounds and cliffs. However, the composition of coordinated activity cliff configurations and their topologies are unknown. Therefore, we have identified all activity cliff configurations formed by currently available bioactive compounds and analyzed them in network representations where activity cliff configurations occur as clusters. The composition, topology, frequency of occurrence, and target distribution of activity cliff clusters have been determined. A limited number of large cliff clusters with unique topologies were identified that were centers of activity cliff formation. These clusters originated from a small number of target sets. However, most clusters were of small to moderate size. Three basic topologies were sufficient to describe recurrent activity cliff cluster motifs/topologies. For example, frequently occurring clusters with star topology determined the scale-free character of the global activity cliff network and represented a characteristic activity cliff configuration. Large clusters with complex topology were often found to contain different combinations of basic topologies. Our study provides a first view of activity cliff configurations formed by currently available bioactive compounds and of the recurrent topologies of activity cliff clusters. Activity cliff clusters of defined topology can be selected, and from compounds forming the clusters, SAR information can be obtained. The SAR information of activity cliff clusters sharing a/one specific activity and topology can be compared.
迄今为止，活性悬崖的评估主要集中在化合物对上，尽管大多数活性悬崖不是孤立形成的，而是以涉及多个活性化合物和悬崖的协调方式形成的。然而，协调活性悬崖结构的组成及其拓扑结构是未知的。因此，我们已经确定了所有由现有生物活性化合物形成的活性悬崖结构，并在网络表示中将它们分析为活动悬崖结构作为集群出现的地方。确定了活性悬崖簇的组成、拓扑、出现频率和靶标分布。确定了具有独特拓扑的有限数量的大型悬崖簇，它们是活性悬崖形成的中心。这些集群源自少数目标集。然而，大多数集群的规模较小或中等。三种基本拓扑足以描述反复出现的活性悬崖簇模式/拓扑。例如，具有星形拓扑的经常出现的集群决定了全局活性悬崖网络的无标度特征，并代表了一种特征性的活性悬崖结构。具有复杂拓扑的大型集群通常包含基本拓扑的不同组合。我们的研究提供了当前可用生物活性化合物形成的活性悬崖结构以及活性悬崖簇的反复出现的拓扑结构的第一视图。可以选择具有定义拓扑的活性悬崖簇，并且可以从形成簇的化合物中获得 SAR 信息。可以比较共享特定活性和拓扑的活性悬崖簇的 SAR 信息。
