Activity cliffs produced by single-atom modification of active compounds: Systematic identification and rationalization based on X-ray structures.

In medicinal chemistry, activity cliffs (ACs) are considered as sources of critical structure-activity relationship (SAR) information. ACs are capable of revealing such SAR information because they are formed by pairs or groups of structural analogs that are distinguished by small chemical modifications leading to large variations in compound potency. Such modifications can reveal critically important substitution sites in analog series. Small AC-encoded chemical changes enable the identification of SAR determinants. In this work, we have searched medicinal chemistry data for most "subtle" ACs in which participating compounds are only distinguished by single-atom modifications. These ACs can be directly associated with lead optimization strategies such as positional atom scanning (atom "walks") or heteroatom replacements in ring structures. More than 1500 of these ACs with activity against a variety of targets were identified. To further explore newly identified ACs, we searched for X-ray structures of ligand-target complexes containing participating AC compounds. For a subset of subtle ACs, X-ray structures of complexes made it possible to examine effects of single-atom changes in light of well-defined ligand-target interactions. Since ACs capturing minimal chemical changes are of particular interest for lead optimization and drug design, we make all newly identified ACs and associated structural information freely available as an open access deposition.