Click Reactions in Kinetic Target-Guided Synthesis: Progress in the Discovery of Inhibitors for Biological Targets

The rapid expansion of click chemistry reflects its transformative influence on contemporary drug discovery. This review highlights major advances in the application of click reactions within the kinetic target-guided synthesis (KTGS) paradigm for identifying potent inhibitors across a broad range of biological targets. KTGS constitutes a methodological shift that leverages the inherent dynamics of biomolecular systems, enabling biological targets to direct the in situ assembly of high-affinity bidentate ligands from a diverse repertoire of reactive building blocks. The review systematically classifies the principal bond-forming reactions that underpin effective inhibitor generation via KTGS. Collectively, it provides a comprehensive and scholarly analysis of how click-chemistry-enabled KTGS is redefining drug discovery and expediting the development of next-generation therapeutics.