Increasing the public activity cliff knowledge base with new categories of activity cliffs

Abstract

Aim: Extending the public knowledge base of activity cliffs (ACs) with new categories of ACs having special structural characteristics. Methodology: Dual-site ACs, isomer ACs and ACs with privileged substructures are described and their systematic identification is detailed. Exemplary results & data: More than 7400 new ACs belonging to different categories with activity against more than 200 targets were identified and are made publicly available. Limitations & next steps: For dual-site ACs, limited numbers of isomers are available as structural analogs for rationalizing contributions to AC formation. The search for such analogs will continue. In addition, the target distribution of ACs containing privileged substructures will be further analyzed. Activity cliffs (ACs) are formed by small molecules that have very similar structures, are active against the same biological target, but have a large difference in potency against their target. Accordingly, ACs are of interest in medicinal chemistry because they reveal small structural changes that greatly influence the potency of active compounds. This information can be used for compound optimization. Computational methods are applied to search for ACs in large compound databases. Here, we further extend the public AC knowledge base with new categories of ACs having special structural characteristics. Shown are an exemplary dual-site activity cliff (AC) (top), isomer AC (middle) and an AC containing a privileged substructure (bottom). Structural differences between AC compounds are highlighted in blue and the privileged substructure is colored pink. Compound targets and potency (pKi) values are reported.