Chemical substitutions that introduce activity cliffs across different compound classes and biological targets.

Applying the concept of matched molecular pairs, we have systematically analyzed the ability of defined chemical changes to introduce activity cliffs. Public domain compound data were systematically screened for matched molecular pairs that were then organized according to chemical transformations they represent and associated potency changes. From vast available chemical transformation space, including both R-group and core substructure changes, approximately 250 nonredundant substitutions were identified that displayed a general tendency to form activity cliffs. These substitutions introduced activity cliffs in the structural context of diverse scaffolds and in compounds active against many different targets. Activity cliff-forming transformations were often rather simple, including replacements of small functional groups. Moreover, in many instances, chemically very similar transformations were identified that had a much lower propensity to form activity cliffs or no detectable cliff potential. Thus, clear preferences emerged for specific transformations. A compendium of substitutions with general activity cliff-forming potential is provided to aid in compound optimization efforts.