Steered molecular dynamics for studying ligand unbinding of ecdysone receptor

<p>Ecdysone receptor (EcR) is an important target for pesticide design. Ligand binding regulates EcR transcriptional activity similar to other nuclear receptors; however, the pathways by which ligands enter and leave the EcR remain poorly understood. Here, we performed computational studies to identify unbinding pathways of an ecdysone agonist [the selective ecdysone agonist, BYI06830] from the EcR ligand binding domain (EcR LBD). BYI06830 can dissociate from EcR LBD via four different pathways with little effect on receptor structure. By comparing the potential of mean force (PMF) of four pathways, path 2 was considered to be the most likely exit path for BYI06830, which was located in the cleft formed by the H3-H4 loop, H6-H7 loop, and the H11 C-terminus. Furthermore, structural features along path 2 were analyzed and the structural snapshots of the metastable and transition states were isolated to illustrate the unbinding mechanism of ecdysone agonist from EcR LBD.</p

Design, Synthesis, and Insecticidal Activity of Novel Isoxazoline Compounds That Contain <i>Meta</i>-diamides against Fall Armyworm (Spodoptera frugiperda)

Fall armyworm (Spodoptera frugiperda) is a major migratory pest around the entire world that causes severe damage to agriculture. We designed and synthesized a series of novel isoxazoline derivatives based on the previously discovered active compound H13 to find new and effective candidates against S. frugiperda. Most of them showed excellent insecticidal activity. In addition, a three-dimensional quantitative structure–activity relationship model was established, and compound F32 was designed and synthesized based on the results. The bioassay result showed that compound F32 exhibited excellent activity against S. frugiperda (LC50 = 3.46 mg/L), which was substantially better than that of the positive control fipronil (LC50 = 78.8 mg/L). Furthermore, an insect γ-aminobutyric acid (GABA) enzyme-linked immunosorbent assay indicated that F32 can upregulate the content of GABA in insects in a manner similar to that of fipronil. Molecular docking showed that the hydrophobic effect and hydrogen-bond interactions are vital factors between the binding of F32 and receptors. All of these results suggest that compound F32 could be employed as a novel isoxazoline lead compound to control S. frugiperda

Structure-Based Virtual Screening, Compound Synthesis, and Bioassay for the Design of Chitinase Inhibitors

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 <i>Of</i>ChtI, a chitinase indispensable for the molting of the insect pest <i>Ostrinia furnacalis</i> (Asian corn borer), here we report a chemical fragment and five variant compounds as inhibitors of <i>Of</i>ChtI 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 <i>Of</i>ChtI-inhibitory activities in a bioassay. Compound <b>3</b> showed preferential inhibitory activity with a <i>K</i>_i value of 1.5 μΜ against <i>Of</i>ChtI. 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

Discovery of Novel Isoxazoline Compounds that Incorporate a <i>para</i>-Diamide Moiety as Potential Insecticidal Agents against Fall Armyworm (Spodoptera frugiperda)

Spodoptera frugiperda is a major migratory agricultural pest, which seriously impedes agricultural production around the world. To discover potent compounds against S. frugiperda, a number of novel isoxazoline derivatives were designed and synthesized and created on account of the identified lead compound F32 (4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(3-propionamidophenyl)benzamide). Based on the three-dimensional quantitative structure–activity relationship of those compounds, the compound G22 (N-(4-acetamidophenyl)-4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide) was developed. A bioassay showed that G22 is highly lethal to S. frugiperda (LC50 = 1.57 mg/L), a more effective control than insecticides fipronil (LC50 = 78.8 mg/L) and chlorantraniliprole (LC50 = 1.60 mg/L). Field trials were also implemented to identify candidate agents. Furthermore, from the insect γ-aminobutyric acid (GABA) enzyme-linked immunosorbent assay, it is obvious that G22 could up-regulate the expression of GABA of insects, which showed a similar result to fipronil. The analysis of molecular docking exhibited that the hydrophobic effect and hydrogen bonds play key roles in the combination between G22 with GABA receptors. This study provides a potent isoxazoline candidate compound for the S. frugiperda control