Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

[Display omitted] •Evaluation of how modifications effect macrocyclic conformations.•Discussion of how macrocycles conformation unpredictably links to activity.•Assessment of heterocycles roles in macrocycles are provided.•Side chain roles in biological activity are reviewed.•A link between stereochemistry and biological activity is demonstrated. Heterocycle-containing macrocycles are an emerging class of molecules that have therapeutic efficacy. Many biologically active natural products that have interesting biological properties fall into this class of molecules. The highly specific and selective biological activity is often attributed to the unique conformation of these macrocycles, which is affected by the elements of the macrocycles as well as its surroundings in biological systems. In this review, the structure–activity relationship studies of several recently developed biologically active heterocycle-containing macrocycles have been discussed in order to facilitate an understanding on how unpredictable structures can be controlled.