Biology-oriented synthesis: harnessing the power of evolution

Abstract

For scientists to gain a better understanding of nature, biological research is greatly aided by small-molecule modulators that perturb protein activity without fundamentally altering the underlying biological systems. The number of possible interfering molecules, however, is so vast that, due to limitations in existing matter and time required for synthesis, they cannot be covered comprehensively. Because proteins and their cognate natural product ligands and substrates co-evolved, these naturally occurring ligands can serve as structural starting points to explore the biologically relevant chemical space. To this end, known natural products are structurally classified on the basis of their core scaffolds and hierarchically arranged in the "natural product tree", which can be annotated for bioactivity and intuitively navigated with currently available software. Biologically relevant scaffolds inspire the synthesis of compound libraries enriched in biological activity. This Perspective describes the development of "biology-oriented synthesis" as a guiding principle to harness the power of evolution in the quest for novel bioactive small molecules for chemical biology research and drug discovery.