Figure 7.

Focused chemical evolution. (1) The cyclic procedure starts with the generation of a “pool of genotypes” which is synthesised from NP fragments (=inheritable chemical information) using synthetic strategies that allow for the combinatorial application of a set of feasible connectivity patterns as well as further derivatisations. (2) Structural properties of the resulting compound library, such as content of sp³‐hybridised atoms, stereocentres, heteroatoms, and aromaticity, account for the expression of “phenotypes”—the potential to interact with specific structural motifs of proteins. (3) The compound library then is applied to a cellular screening platform (e.g., yeast cells) which is optically monitored for structural changes, e.g., by fluorescence imaging. Data are combined, analysed, and sorted according to selective constraints. (4) Molecules causing a desired change in the cellular system are isolated and identified (NMR, MS) and submitted to further structural characterisation, for example, by co‐crystallisation with putative target proteins (example used here: 4PYP^[67]). The outcome of this round is the beginning of a new cycle which includes the “new chemical information” that was received.