Targeting Metalloenzymes by Boron-Containing Metal-Binding Pharmacophores

Metalloenzymes have critical roles in a wide range of biological processes and are directly involved in many human diseases; hence, they are considered as important targets for therapeutic intervention. The specific characteristics of metal ion(s)-containing active sites make exploitation of metal-binding pharmacophores (MBPs) critical to inhibitor development targeting metalloenzymes. This Perspective focuses on boron-containing MBPs, which display unique binding modes with metalloenzyme active sites, particularly via mimicking native substrates or tetrahedral transition states. The design concepts regarding boron-containing MBPs are highlighted through the case analyses on five distinct classes of clinically relevant nucleophilic metalloenzymes from medicinal chemistry perspectives. The challenges (e.g., selectivity) faced by some boron-containing MBPs and possible strategies (e.g., bioisosteres for metalloenzyme inhibitor transformation are also discussed.

Automated summary

Metalloenzymes play critical roles in biological processes and are important therapeutic targets. This perspective focuses on the importance of exploiting metal-binding pharmacophores, specifically boron-containing MBPs, in inhibitor development targeting metalloenzymes. The challenges and design concepts regarding boron-containing MBPs are discussed, with emphasis on the unique binding modes with metalloenzyme active sites.