Metalloprotein-Targeted Inhibitors: A Promising Strategy for Novel Pesticide Discovery

Pesticides contribute to food security. Meanwhile, many traditional pesticides have lost their effectiveness and caused adverse impacts on the environment due to the growing resistance problem. There is an urgent need to develop pesticides with novel modes of action. Metalloproteins, generally enzymes containing functionally or structurally essential metal ions, have attracted more and more attention as promising molecular targets for pesticide development because of their wide involvement in key physiological processes of weeds, phytopathogens, and pests. Up to now, some ligands targeting metalloproteins have been approved as pesticides and exhibit promising effects. However, a systematic insight into the metalloprotein-targeted strategy for pesticide discovery is still lacking. In this study, we comprehensively investigated metalloproteins that have been used for pesticide development or shown potential as novel pesticide targets, including their biological functions, protein structures, active-site features, and targeted ligands. Further, we discuss the metal-binding pharmacophores in metalloprotein ligands that lead to bioactivity at the enzyme or agricultural organism level. Finally, the computational methods used in metalloprotein ligand design are summarized. This study aims to provide clues and insights into the development of novel pesticide candidates targeting metalloproteins.