Second-generation Activity Cliffs Identified on the Basis of Target set-dependent Potency Difference Criteria
Huabin Hu, Dagmar Stumpfe, Jürgen Bajorath · Future Medicinal Chemistry · 2019
AIM: Activity cliffs (ACs) are formed by structurally similar compounds with large potency differences. Accordingly, ACs reveal determinants of structure-activity relationships. This makes ACs highly interesting and relevant for medicinal chemistry and chemoinformatics. So far, ACs have been defined on the basis of generally applied molecular similarity and potency difference criteria. RESULTS: We present the first assessment of ACs taking target set-dependent compound potency distributions into account, leading to a new target set-dependent definition of ACs. The formation of these ACs is analyzed in detail. CONCLUSION: Second-generation ACs are obtained on the basis of target set-dependent potency difference thresholds. Compared with generally defined ACs, target set-dependent ACs have further increased medicinal chemistry relevance.