Computational Modeling Oriented Substructure Splicing Application in the Identification of Thiazolidine Derivatives as Potential Low Honeybee Toxic Neonicotinoids.

With the aim of identifying novel neonicotinoid insecticides with low bee toxicity, a series of compounds bearing thiazolidine moiety, which has been shown to be low bee toxic, were rationally designed through substructure splicing strategy and evaluated insecticidal activities. The optimal compounds A24 and A29 exhibited LC50 values of 30.01 and 17.08 mg/L against Aphis craccivora, respectively. Electrophysiological studies performed on Xenopus oocytes indicated that compound A29 acted on insect nAChR, with EC50 value of 50.11 µM. Docking binding mode analysis demonstrated that A29 bound to Lymnaea stagnalis acetylcholine binding protein through H-bonds with the residues of D_Arg55, D_Leu102, and D_Val114. Quantum mechanics calculation showed that A29 had a higher highest occupied molecular orbit (HOMO) energy and lower vertical ionization potential (IP) value compared to the high bee toxic imidacloprid, showing potentially low bee toxicity. Bee toxicity predictive model also indicated that A29 was nontoxic to honeybees. Our present work identified an innovative insecticidal scaffold and might facilitate the further exploration of low bee toxic neonicotinoid insecticides.

Discovery of Potential Neonicotinoid Insecticides by an Artificial Intelligence Generative Model and Structure-Based Virtual Screening.

The identification of neonicotinoid insecticides bearing novel scaffolds is of great importance for pesticide discovery. Here, artificial intelligence-based tools and virtual screening strategy were integrated to discover potential leads of neonicotinoid insecticides. A deep generative model was successfully constructed using a recurrent neural network combined with transfer learning. The model evaluation showed that the pretrained model could accurately grasp the SMILES grammar of drug-like molecules and generate potential neonicotinoid compounds after transfer learning. The generated molecules were evaluated by hierarchical virtual screening, hits were subjected to a similarity search, and the most similar structures were purchased for the bioassay. Compounds A2 and A5 displayed 52.5 and 50.3% mortality rates against Aphis craccivora at 100 mg/L, respectively. The docking study indicated that these two compounds have similar binding modes to neonicotinoids, which were verified by further molecular dynamics simulations.

Design, Synthesis, and Insecticidal Evaluation of Neonicotinoids with Conjugated Diene.

Neonicotinoid insecticides acting on the insect nicotinic acetylcholine receptors (nAChRs) play an essential role in contemporary pest control. In the present study, a series of novel neonicotinoid analogues with conjugated diene were synthesized. Bioassays indicated that compounds A3 and A12 had LC50 values of 1.26 and 1.24 mg/L against Myzus persicae, respectively, which were comparable to that of imidacloprid (IMI, LC50 = 0.78 mg/L). Density functional theory (DFT) calculations were performed to explain the differences in the insecticidal activities of target compounds. Molecular docking results indicate that compounds A3 and A12 interact favorably with Lymnaea stagnalis AChBP. The hydrolysis experiments confirmed that the stability of compounds A3 and A12 was enhanced in water.

Design, Synthesis, and Insecticidal Activities of Novel N-Pyridylpyrazole Amide Derivatives Containing a Maleimide.

To discover 'me-better' insecticidal active molecules targeting ryanodine receptors (RyRs), a series of novel N-pyridylpyrazole amide derivatives containing a maleimide were designed and synthesized in accordance with the prior investigations of our group. Preliminary bioassay findings indicated some compounds containing a maleimide exhibited good larvicidal activities against lepidopteran pests at a concentration of 500 mg L-1 . Compound 9 j showed 60 % larvicidal activities against M. Separata at 50 mg L-1 . Compound 9 b exhibited 40 % larvicidal activities against P. xylostella at 50 mg L-1 . Molecular docking study indicated that H-bonds, π-π interaction and cation-π interaction made for the binding of compounds 9 b, 9 j with P. Xylostella RyR. These results indicated that compounds 9 b and 9 j could be developed as novel and promising insecticidal leads.

Mechanism of the distinct toxicity level of imidacloprid and thiacloprid against honey bees: An in silico study based on cytochrome P450 9Q3.

The honey bee, Apis mellifera, shows variation in sensitivity to imidacloprid and thiacloprid, which does not reside at the target site but rather in the rapidly oxidative metabolism mediated by P450s (such as a single P450, CYP9Q3). An in silico study was conducted to investigate the various metabolism of imidacloprid and thiacloprid. The binding potency of thiacloprid was stronger and a stable π-π interaction with Phe121 and the N-H⋯N hydrogen bond with Asn214 are found in the CYP9Q3-thiacloprid system but absent in imidacloprid, which might affect the potential metabolic activity. Moreover, the values of highest occupied molecular orbit (HOMO) energy and the vertical ionization potential (IP) of two compounds demonstrated that thiacloprid is more likely to oxidation. The findings revealed the probable binding modes of imidacloprid and thiacloprid with CYP9Q3 and might facilitate future design of the low bee toxicity neonicotinoid insecticides.

Study on the mode of action between Apis mellifera (α8)2(ß1)3 nAChR and typical neonicotinoids versus flupyradifurone with different bee-toxic levels.

The health of bee populations worldwide is affected by multiple factors, of which neonicotinoids are considered to be a main reason. Although most neonicotinoids are highly toxic to bees, some of them are relatively safe. To explore the molecular mechanism of these differences in toxicity, homology modelling, molecular docking and molecular dynamics simulations were applied to study the interactions between Apis mellifera (α8)2(ß1)3 nAChR and high bee-toxic neonicotinoid (imidacloprid, IMI), medium bee-toxic (thiacloprid, THI) and low bee-toxic butenolides (flupyradifurone, FPF). It was observed that three major interactions were similar across all systems, including water-bridge networks, π-π interactions and the polar interactions between the electron-withdrawing pharmacophores and the receptor. The calculated binding free energy was similar between IMI and THI. While FPF was the lowest bee-toxic, it displayed the strongest binding free energy value, the additional C-H⋯O H-bonds with Arg80 and Trp179 were the main reason. The bee toxicities of neonicotinoids and other nAChR modulators are not only determined by receptor affinities, but also by other factors (for example physicochemical properties and metabolic detoxification). All influencing factors should be fully considered in the future design of new eco-friendly insecticides that are safe for bees.