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.
Quantitative structure−activity relationship (QSAR) modeling can be used to predict the toxicity of ionic liquids (ILs), but most QSAR models have been constructed by arbitrarily selecting one machine learning method and ignored the overall interactions between ILs and biological systems, such as proteins. In order to obtain more reliable and interpretable QSAR models and reveal the related molecular mechanism, we performed a systematic analysis of acetylcholinesterase (AChE) inhibition by 153 ILs using machine learning and molecular modeling. Our results showed that more reliable and stable QSAR models (R 2 > 0.85 for both cross-validation and external validation) were obtained by combining the results from multiple machine learning approaches. In addition, molecular docking results revealed that the cations and organic anions of ILs bound to specific amino acid residues of AChE through noncovalent interactions such as π interactions and hydrogen bonds. The calculation results of binding free energy showed that an electrostatic interaction (ΔE ele < −285 kJ/ mol) was the main driving force for the binding of ILs to AChE. The overall findings from this investigation demonstrate that a systematic approach is much more convincing. Future research in this direction will help design the next generation of biosafe ILs.
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.
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