Stereochemical diversity as a source of discovery in chemical biology

Chirality is an inherent aspect of biology, and interactions between biomolecules are often influenced by stereochemistry and topographic complexity. This has implications for how small-molecule libraries are assembled for screening campaigns in chemical biology and drug discovery. Here we review the state of the field in the context of harnessing chirality as a source of chemical information at the chemistry-biology interface. We further highlight the emergence of screening libraries containing stereoisomeric sets of compounds and the concept of using stereoselectivity of phenotype and/or target engagement as a way to prioritize actionable targets and streamline the identification of selective and potent modulators of disease-relevant biomolecules. The chemical information density of FDA-approved drugs and the effect of stereochemistry on molecular complexity are reported. Finally, axial chirality and atroposelectivity are discussed as potential expansions of the aforementioned concepts.