Abiotic scaffolds in medicinal chemistry: not a waste of chemical space

It is well established that medicinal chemists should depart from the flat, sp²-dominated nature of traditional drugs and incorporate complexities of bioactive natural products, such as sp³-richness, 3D topology and chirality. There is a gray area, however, in the relevance of newly developed chemical scaffolds that exhibit these complexities but do not correlate to anything observed in nature. This can leave synthetic methodologists searching for structural similarities between their newly developed products and known natural products in search of justification. This article offers a perspective on how these types of complex 'abiotic' scaffolds can be appreciated purely on the basis of their structural novelty, and identifies the unique advantages arising when a complex chemical entity unrecognized by nature is introduced to biological systems.