Identification of novel nematode succinate dehydrogenase inhibitors: Virtual screening based on ligand-pocket
Qingbo Xu1, Zhixiang Zhao1, Peibo Liang1
1Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, China.
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 IC50 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.
