Stereochemical diversity as a source of discovery in chemical biology
2022
Kevin A. Scott | Nathalie Ropek | Bruno Melillo | Stuart L. Schreiber | Benjamin F. Cravatt | Ekaterina V. Vinogradova
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.
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