Systematic characterization of structure–activity relationships and ADMET compliance: a case study

• Assessment of the effects of structural changes on activity and ADMET properties.
• ADMET ‘violation bit vectors’ used to analyze pairwise ADMET property violations.
• Simultaneous analysis of structure, activity and ADMET similarities is feasible.

Traditionally, activity landscape modeling has been focused on analyzing SAR, despite the fact that lead optimization in drug discovery involves concurrent enhancements of activity and ADMET properties of leads. As a case study, we discuss the systematic analysis of activity landscapes, incorporating ADMET considerations, using a dataset of 166 compounds screened for kappa-opioid receptor activity. Pairwise MACCS/Tanimoto structure similarities, property similarities utilizing 33 ADMET descriptors and a 35-dimensional ‘violation bit vector’ representing drug-likeness are analyzed. We address the question about the range of ADMET property violations that arise from structural changes, subtle and significant. Pairs of compounds are identified bearing identical, comparable and significantly different drug-likeness in the three informative regions of structure–activity landscapes.