Exploring SAR continuity in the vicinity of activity cliffs

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.