Identification of novel nematode succinate dehydrogenase inhibitors: Virtual screening based on ligand‐pocket interactions
Qingbo Xu, Zhixiang Zhao, Peibo Liang, Simin Wang, Fang Li, Shuhui Jin, Jianjun Zhang
Abstract
Abstract To discover new nematicidal succinate dehydrogenase (SDH) inhibitors with novel structures, we conducted a virtual screening of the ChemBridge library with 1.7 million compounds based on ligand‐pocket interactions. The homology model of Caenorhabditis elegans SDH was established, along with a pharmacophore model based on ligand‐pocket interactions. After the pharmacophore‐based and docking‐based screening, 19 compounds were selected for the subsequent enzymatic assays. The results showed that compound 1 (ID: 7607321) exhibited inhibitory activity against SDH with a determined IC 50 value of 19.6 μM. Structural modifications and nematicidal activity studies were then carried out, which provided further evidence that compound 1 exhibited excellent nematicidal activity. Molecular dynamics simulations were then conducted to investigate the underlying molecular basis for the potency of these inhibitors against SDH. This work provides a reliable strategy and useful information for the future design of nematode SDH inhibitors.