Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, Dahlmannstr. 2, D-53113 Bonn, Germany.
Chem Biol Drug Des. 2011 Nov;78(5):778-86. doi: 10.1111/j.1747-0285.2011.01235.x. Epub 2011 Oct 5.
Activity landscape representations provide access to structure-activity relationships information in compound data sets. In general, activity landscape models integrate molecular similarity relationships with biological activity data. Typically, activity against a single target is monitored. However, for steadily increasing numbers of compounds, activity against multiple targets is reported, resulting in an opportunity, and often a need, to explore multi-target structure-activity relationships. It would be attractive to utilize activity landscape representations to aid in this process, but the design of activity landscapes for multiple targets is a complicated task. Only recently has a first multi-target landscape model been introduced, consisting of an annotated compound network focused on the systematic detection of activity cliffs. Herein, we report a conceptually different multi-target activity landscape design that is based on a 2D projection of chemical reference space using self-organizing maps and encodes compounds as arrays of pair-wise target activity relationships. In this context, we introduce the concept of discontinuity in multi-target activity space. The well-ordered activity landscape model highlights centers of discontinuity in activity space and is straightforward to interpret. It has been applied to analyze compound data sets with three, four, and five target annotations and identify multi-target structure-activity relationships determinants in analog series.
活性景观表示法提供了对化合物数据集结构-活性关系信息的访问。通常，活性景观模型将分子相似性关系与生物活性数据集成在一起。通常，监测针对单个靶标的活性。然而，随着化合物数量的稳步增加，针对多个靶标的活性也有报道，这为探索多靶标结构-活性关系提供了机会，而且通常也有必要。利用活性景观表示法来辅助这一过程将是很有吸引力的，但是设计针对多个靶标的活性景观是一项复杂的任务。直到最近，才引入了第一个多靶标景观模型，该模型由一个针对活性悬崖系统检测的注释化合物网络组成。在这里，我们报告了一种基于自组织映射的化学参考空间 2D 投影的概念性不同的多靶标活性景观设计，该设计将化合物编码为成对靶标活性关系的数组。在此上下文中，我们引入了多靶标活性空间中不连续性的概念。有序的活性景观模型突出了活性空间中的不连续性中心，并且易于解释。它已被应用于分析具有三个、四个和五个靶标注释的化合物数据集，并识别类似系列中的多靶标结构-活性关系决定因素。
