Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, Dahlmannstrasse 2, Germany.
Chem Biol Drug Des. 2012 Jan;79(1):22-9. doi: 10.1111/j.1747-0285.2011.01256.x. Epub 2011 Nov 8.
Activity cliffs are formed by structurally similar compounds with significant differences in potency and represent an extreme form of structure-activity relationships discontinuity. By contrast, regions of structure-activity relationships continuity in compound data sets result from the presence of structurally increasingly diverse compounds retaining similar activity. Previous studies have revealed that structure-activity relationships information extracted from large compound data sets is often heterogeneous in nature containing both continuous and discontinuous structure-activity relationships components. Structure-activity relationships discontinuity and continuity are often represented by different compound series, independent of each other. Here, we have searched different compound data sets for the presence of structure-activity relationships continuity within the vicinity of prominent activity cliffs. For this purpose, we have designed and implemented a computational approach utilizing particle swarm optimization to examine the structural neighborhood of activity cliffs for continuous structure-activity relationships components. Structure-activity relationships continuity in the structural neighborhood of activity cliffs was relatively rarely observed. However, in a number of cases, notable structure-activity relationships continuity was detected in the vicinity of prominent activity cliffs. Exemplary local structure-activity relationships environments displaying these characteristics were analyzed in detail. Thus, the structure-activity relationships environment of activity cliffs must not necessarily be discontinuous in nature, and local structure-activity relationships continuity and discontinuity can occur in a concerted manner in series of structurally related compounds.
活性悬崖是由结构相似但效力有显著差异的化合物形成的，代表了结构-活性关系不连续性的极端形式。相比之下，化合物数据集的结构-活性关系连续区域是由具有相似活性的结构逐渐多样化的化合物的存在产生的。先前的研究表明，从大型化合物数据集提取的结构-活性关系信息通常在性质上是异构的，包含连续和不连续的结构-活性关系成分。结构-活性关系的不连续性和连续性通常由不同的化合物系列表示，彼此独立。在这里，我们在不同的化合物数据集附近搜索了活性悬崖附近的结构-活性关系连续性。为此，我们设计并实施了一种利用粒子群优化的计算方法，用于检查活性悬崖附近的结构邻域中连续的结构-活性关系成分。在活性悬崖的结构邻域中很少观察到结构-活性关系的连续性。然而，在许多情况下，在显著的活性悬崖附近检测到了显著的结构-活性关系连续性。详细分析了显示这些特征的典型局部结构-活性关系环境。因此，活性悬崖的结构-活性关系环境不一定具有不连续性，局部结构-活性关系的连续性和不连续性可以在结构相关化合物系列中协同发生。
