Chitinases play a vital part in the molting phase of insect pests. Inhibiting their activities by the use of drug-like small chemical molecules is thought to be an efficient strategy in pesticide design and development. On the basis of the crystal structure of OfChtI, a chitinase indispensable for the molting of the insect pest Ostrinia furnacalis (Asian corn borer), here we report a chemical fragment and five variant compounds as inhibitors of OfChtI obtained from a library of over 200 000 chemicals by a structure-based-virtual-screening approach. The compounds were synthesized with high atom economy and tested for their OfChtI-inhibitory activities in a bioassay. Compound 3 showed preferential inhibitory activity with a K value of 1.5 μΜ against OfChtI. Analysis of the structure-activity relationships of the compounds provided insight into their interactions with the enzyme active site, which may inform future work in improving the potencies of their inhibitory activities.

Insect chitinases play an indispensable role in shedding old cuticle during molting. Targeting chitinase inhibition is a promising pest control strategy. Of ChtI, a chitinase from the destructive insect pest Ostrinia furnacalis (Asian corn borer), has been suggested as a potential target for designing green pesticides. A 4,5,6,7-tetrahydrobenzo­[b]­thiophene-3-carboxylate scaffold was previously obtained, and further derivatization generated the lead compound 1 as Of ChtI inhibitor. Here, based on the predicted binding mode of compound 1, the pocket-based lead optimization strategy was applied. A series of analogues was synthesized, and their inhibitory activities against Of ChtI were evaluated. Compound 8 with 6-tert-pentyl showed preferential inhibitory activity with a K i value of 0.71 μM. Their structure–activity relationships suggested that the compound with larger steric hindrance at the 6-nonpolar group was essential for inhibitory activity due to its stronger interactions with surrounding amino acids. This work provides a strategy for designing potential chitinase inhibitors.

Background and Purpose Like chili peppers, gingers produce pungent stimuli by a group of vanilloid compounds that activate the nociceptive transient receptor potential vanilloid 1 (TRPV1) ion channel. How these compounds interact with TRPV1 remains unclear. Experimental Approach We used computational structural modelling, functional tests (electrophysiology and calcium imaging), and mutagenesis to investigate the structural mechanisms underlying ligand–channel interactions. Key Results The potency of three principal pungent compounds from ginger —shogaol, gingerol, and zingerone—depends on the same two residues in the TRPV1 channel that form a hydrogen bond with the chili pepper pungent compound, capsaicin. Computational modelling revealed binding poses of these ginger compounds similar to those of capsaicin, including a “head‐down tail‐up” orientation, two specific hydrogen bonds, and important contributions of van der Waals interactions by the aliphatic tail. Our study also identified a novel horizontal binding pose of zingerone that allows it to directly interact with the channel pore when bound inside the ligand‐binding pocket. These observations offer a molecular level explanation for how unique structures in the ginger compounds affect their channel activation potency. Conclusions and Implications Mechanistic insights into the interactions of ginger compounds and the TRPV1 cation channel should help guide drug discovery efforts to modulate nociception.

Insect growth regulators (IGRs) can cause abnormal growth and development in insects, resulting in incomplete metamorphosis or even death of the larvae. Ecdysone receptor (EcR) and chitinase in insects play indispensable roles in the molting process. Ecdysone analogues and chitinase inhibitors are considered as potential IGRs. In order to find new and highly effective IGR candidates, based on the structure–activity relationship and molecular docking results of the active compound 6i (3-(tert-butyl)-N-(4-(tert-butyl)­phenyl)-1-phenyl-1H-pyrazole-5-carboxamide) discovered in our previous work, we changed the t-butyl group on the pyrazole ring into heptacycle to enhance the hydrophobicity. Consequently, a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized. The bioassay results demonstrated that some compounds showed obvious insecticidal activity. Especially, D-27 (N-(4-(tert-butyl)­phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta­[c]­pyrazole-5-carboxamide) showed good activities against Plutella xylostella (LC50, 51.50 mg·L–1) and Mythimna separata (100% mortality at 2.5 mg·L–1). Furthermore, protein validation indicated that D-27 acts not only on the EcR but also on chitinase Of ChtI. Molecular docking and molecular dynamics simulation explained the vital factors in the interaction between D-27 and receptors. D-27 may be a new lead candidate with a dual target in which Of ChtI shall be the main one. This work created a new starting point for discovering a novel type of IGRs.

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