Multitarget Structure–Activity Relationships Characterized by Activity-Difference Maps and Consensus Similarity Measure

Abstract

Dual and triple activity-difference (DAD/TAD) maps are tools for the systematic characterization of structure-activity relationships (SAR) of compound data sets screened against two or three targets. DAD and TAD maps are two- and three- dimensional representations of the pairwise activity differences of compound data sets, respectively. Adding pairwise structural similarity information into these maps readily reveals activity cliff regions in the SAR for one, two, or three targets. In addition, pairs of compounds in the smooth regions of the SAR and scaffold hops are also easily identified in these maps. Herein, DAD and TAD maps are employed for the systematic characterization of the SAR of a benchmark set of 299 compounds screened against dopamine, norepinephrine, and serotonin transporters. To reduce the well-known dependence of the activity landscape on the structural representation, five selected 2D and 3D structure representations were used to characterize the SAR. Systematic analysis of the DAD and TAD maps reveals regions in the landscape with similar SAR for two or the three targets as well as regions with inverse SAR, i.e., changes in structure that increase activity for one target, but decrease activity for the other target. Focusing the analysis on pairs of compounds with high structure similarity revealed the presence of single-, dual-, and triple-target activity cliffs, i.e., small changes in structure with high changes in potency for one, two, or the three targets, respectively. Triple-target scaffold hops are also discussed. Activity cliffs and scaffold hops were also quantified and represented using two recently proposed approaches namely, mean Structure Activity Landscape Index (mean SALI) and Consensus Structure-Activity Similarity (SAS) maps.

CASE Plots for the Chemotype‐Based Activity and Selectivity Analysis: A CASE Study of Cyclooxygenase Inhibitors

“…Dual activity-difference maps were previously reported as a useful tool to characterize multitarget SAR (11,12). This method has been applied previously for databases where compounds share the same scaffold (11) as well for structurally diverse compounds (12,13).…”

“…Dual activity-difference maps were previously reported as a useful tool to characterize multitarget SAR (11,12). This method has been applied previously for databases where compounds share the same scaffold (11) as well for structurally diverse compounds (12,13). Dual activity-difference maps were divided in five regions Z1-Z5 (see prototype map in Figure 3) using a threshold in activity potency differences of €1 in pIC 50 as detailed in the Methods (other threshold values can be used).…”

“…The SAR of data sets tested against two biological end-points, for example molecular targets I and II, can be characterized using DAD maps which are based on pairwise comparisons (11)(12)(13). For a data set of N compounds tested against targets I and II, the DAD map depicts N(N-1) ⁄ 2 pairwise potency differences corresponding to each possible pair of compounds in the data set against both targets.…”

“…Of note, the classification of data points in an activity-difference map is independent of the structure similarity. Further details of DAD maps are described elsewhere (11)(12)(13).…”

“…Based on the fact that the chemotype analysis does not consider the side chains of the molecules, which are also crucial for the biological activity, we extended the analysis to include the entire molecules. For this purpose, selected chemotypes identified in the CASE plot were further analyzed using the previously described dual activity-difference (DAD) maps (11)(12)(13), which are two-dimensional representations of the pairwise activity differences designed to characterize activity landscapes of data sets with biological activity against two biological end-points (11)(12)(13). It is worth to notice that DAD maps uncover regions in the landscape with similar SAR for two receptor subtypes as well as regions with inverse SAR (11-13).…”