Probing secondary interactions in biomolecular recognition by dynamic combinatorial chemistry

Artificial multivalent recognition systems offer promising perspectives for developing synthetic compounds capable of interacting effectively and selectively with biomolecules in aqueous medium. The identification of multi-point binding ligands requires screening of a large number of complex structures, with different spacers, different ligands, and varying valency. This represents a challenge for rational design approaches. On the other hand, the use of dynamic covalent chemistry enables a target-driven one-pot screening approach for probing secondary interactions, thereby facilitating the identification of multivalent recognition systems that optimally combine multiple fragments. Herein we review the recent developments in the implementation of dynamic combinatorial chemistry for probing secondary interactions and thereby identify multi-point binding ligands of biomolecules.