Discovery of Novel Inhibitors Targeting Fungal Chitin Deacetylase via Virtual Screening for Plant Disease Control

Fungal chitin deacetylase (CDA) plays a crucial role in pathogen-plant interactions, which is regarded as an innovative and promising target for fungicides. In this study, a pharmacophore-based virtual screening strategy was employed to identify compounds <b>VS-24</b> and <b>VS-25</b> as potent inhibitors against <i>Puccinia striiformis</i> f. sp. <i>tritici</i> CDA (<i>Pst</i>CDA). Further bioassays demonstrated that <b>VS-24</b> exhibited a protective effect of 61.2% against rice blast at 100 μg/mL, while <b>VS-25</b> showed a superior protective effect of 45.5% against corn rust at 5 μg/mL, both superior to the reported CDA inhibitor benzohydroxamic acid (BHA). Molecular dynamics simulations revealed that multiple key interactions involving the Zn²⁺ ion and residues His207 and Tyr152 of <i>Pst</i>CDA are critical for the binding of <b>VS-24</b> or <b>VS-25</b>, with electrostatic interactions contributing most significantly to the binding free energy. Finally, toxicity predictions confirmed the potential biosafety of <b>VS-24</b> and <b>VS-25</b>. Overall, this study identified two promising lead compounds targeting fungal CDA to control plant diseases.