Kinetic target-guided synthesis.

In the last decade, various target-guided synthesis (TGS) approaches have been developed in which a target protein is actively engaged in the assembly of its own bidentate ligand from a pool of smaller reactive fragments. Although TGS is relatively less explored, it demonstrates great promise to streamline drug discovery by combining screening and synthesis into a single step. Herein, we focus on the class of kinetic TGS approaches which utilize irreversible reactions to combine two reactive fragments into the inhibitory compound. These kinetic TGS applications have been successful due to the unique combination of the slow nature of the chemical reaction combining the two fragments into a single molecule and the use of reactive fragments displaying good affinities toward one of the binding sites. So far, kinetic TGS and especially in situ click chemistry, a kinetic TGS variant using the 1,3-dipolar cycloaddition of azides and alkynes, have led to the identification of highly potent inhibitors. This tutorial review focuses on kinetic TGS approaches aside from those employing the 1,3-dipolar cycloaddition of azides and alkynes, and discusses the features and advantages of these TGS approaches in detail.