Omeprazole and its analogs exhibit insecticidal potencies as inhibitors of insect choline acetyltransferase.

Choline acetyltransferase (ChAT) is crucial for acetylcholine synthesis and regulates diverse functions in numerous biological processes. Omeprazole, an inhibitor on human ChAT, was evaluated here on insect ChAT as a potential inhibitor, as well as its insecticidal potency on Nilaparvata lugens, a major insect pest on rice. The evaluation also included omeprazole analogs and α-NETA, in order to explore a superior leading compound targeting on insect ChAT. In toxicity test, α-NETA and omeprazole exhibited insecticidal activity, among which omeprazole exhibited activity with a mortality of around 50 % on N. lugens nymphs at 0.4 mg/mL. In vitro crude enzyme assays showed that omeprazole acted as an inhibitor on insect ChAT with a high selectivity and exciting potency compared with α-NETA and control. Three residues (Tyr84, Val95, Tyr589) was critical in N. lugens ChAT for interacting with its substrate choline through molecular docking, and it also revealed that omeprazole exhibited a higher binding affinity toward ChAT catalytic tunnel compared with α-NETA. Based on this, we screened omeprazole analogs for their affinity to N. lugens ChAT, and two compounds stood out. The 5-hydroxy omeprazole had the highest binding affinity by prediction, and 5-O-desmethyl omeprazole was with the lowest binding affinity. The toxicity bioassay and enzyme activity test were then performed on these two compounds. Aligned with the docking results, 5-hydroxy omeprazole showed a strong inhibitory effect and insecticidal activity. In summary, omeprazole and 5-hydroxy omeprazole could serve as lead compounds for insecticides targeting on insect ChAT, a novel target.