Rationalizing Three-Dimensional Activity Landscapes and the Influence of Molecular Representations on Landscape Topology and the Formation of Activity Cliffs

Activity landscapes are defined by potency and similarity distributions of active compounds and reflect the nature of structure−activity relationships (SARs). Three-dimensional (3D) activity landscapes are reminiscent of topographical maps and particularly intuitive representations of compound similarity and potency distributions. From their topologies, SAR characteristics can be deduced. Accordingly, idealized theoretical landscape models have been utilized to rationalize SAR features, but “true” 3D activity landscapes have not yet been described in detail. Herein we present a computational approach to derive approximate 3D activity landscapes for actual compound data sets and to analyze exemplary landscape representations. These activity landscapes are generated within a consistent reference frame so that they can be compared across different activity classes. We show that SAR features of compound data sets can be derived from the topology of landscape models. A notable correlation is observed between global SAR phenotypes, assigned on the basis of SAR discontinuity scoring, and characteristic landscape topologies. We also show that different molecular representations can substantially alter the topology of activity landscapes for a given data set and modulate the formation of activity cliffs, which represent the most prominent landscape features. Depending on the choice of molecular representations, compounds forming a steep activity cliff in a given landscape might be separated in another and no longer form a cliff. However, comparison of alternative activity landscapes makes it possible to focus on compound subsets having high SAR information content.