Rationalizing Promiscuity Cliffs

Compound promiscuity can be viewed in different ways. We distinguish “bad” promiscuity resulting from chemical liabilities, nonspecific binding, or assay artifacts, from “good” promiscuity representing true multitarget activities. Investigating multitarget activities of small molecules is scientifically stimulating and therapeutically relevant. To better understand the molecular basis of multitarget activities, structure‐promiscuity relationships (SPRs) are explored. For this purpose, “promiscuity cliffs” (PCs) have been introduced, which can be rationalized as an extension of the activity cliff (AC) concept. A PC is defined as a pair of structural analogues that are active against different numbers of targets (given a difference threshold). As discussed herein PCs frequently capture surprising SPRs and encode many experimentally testable hypotheses.