Evolving Concept of Activity Cliffs

Activity cliffs (ACs) are generally defined as pairs or groups of structurally similar compounds that are active against the same target but have large differences in potency. Accordingly, ACs capture chemical modifications that strongly influence biological activity. Therefore, they are of particular interest in structure–activity relationship (SAR) analysis and compound optimization. The AC concept is much more complex than it may appear at a first glance, especially if one aims to represent ACs computationally and identify them systematically. To these ends, molecular similarity and potency difference criteria must be carefully considered for AC assessment. Furthermore, ACs are often perceived differently in medicinal and computational chemistry, depending on whether they are studied on a case-by-case basis or systematically. For practical applications, intuitive access to AC information plays a major role. Over the years, the AC concept has been further refined and extended. Herein, we review the evolution of the AC concept, emphasizing new analysis schemes and findings that help to better understand ACs and extract SAR knowledge from them.