Disruptions in bioactivity driven by dose: a challenge for drug discovery

Abstract

Dose-driven disruptions in bioactivity challenge traditional, structure-focused drug discovery, which often overlooks effects beyond structural factors. Whereas classical dose–response describes quantitative changes in the magnitude of a given effect, evidence shows that many compounds also display biphasic or inverted dose–response profiles and, by extension, dose-dependent shifts in activity type. These phenomena can cause abrupt potency transitions, or even qualitative activity switches, akin to structural activity cliffs, but driven by concentration. Incorporating such effects into activity prediction models (APMs) requires nonlinear modeling, biologically contextualized data sets, and biomacromolecule-focused classification. Recognizing that biological systems exhibit both gradual dose–response behaviors and disruptive, concentration-dependent activity switches will enhance predictive accuracy and guide the development of mechanism-informed drug discovery pipelines.