Chemical methodologies for Direct-to-Biology library synthesis

The Direct-to-Biology (D2B) paradigm represents a transformative shift in drug discovery, bypassing traditional purification to enable direct biological screening of crude reaction mixtures. Successful D2B implementation demands a holistic strategy that moves beyond yield to assess biocompatibility, miniaturized operational feasibility, and analytical validation. This review first outlines critical factors for D2B library setup, then systematically categorizes reported chemical methodologies into single-step reactions (such as amide couplings, click chemistry, multicomponent reactions, and nucleophilic substitutions, among others) and multi-step approaches (including telescoped liquid-phase sequences as well as solid-phase and solid-liquid combined strategies). By dramatically accelerating the "design-make-test" cycle, D2B platforms are poised to unlock unprecedented chemical space and establish intelligent, self-optimizing discovery ecosystems, ultimately expediting the delivery of novel therapeutics.