Specificity of Monoterpene Interactions with Insect Octopamine and Tyramine Receptors: Insights from in Silico Sequence and Structure Comparison

[Image: see text] Octopamine and tyramine receptors (OARs/TARs) are interesting targets for new insecticide development due to their unique roles in insects’ physiological and cellular response and their specificity to invertebrates. Monoterpene compounds that bear resemblance to the natural ligands have been shown to bind to the OARs/TARs but elicit varied responses in different insect species. Using in silico methods, we attempt to investigate the molecular basis of monoterpene interactions and their specificity in different OARs and TARs of damaging or beneficial insects. Sequence and structure comparison revealed that the OARs/TARs studied generally have more similarities in terms of structure rather than sequence identity. Together with clustering and network analyses, we also revealed that the role of IL3 might be crucial in the identification of OAR and TAR and their unique function. Among the 35 monoterpenes subjected to ensemble docking, carvacrol had the most negative average binding energies with the target insect OARs and TARs. The differences in the key interacting residues of carvacrol with insect OARs and TARs could be the origin of variation in the responses of insect species to this monoterpene. Results suggest that carvacrol may be a potential natural-product-based insecticide, targeting multiple insect pests while being nonharmful to honeybees and Asian swallowtail butterflies. This work could provide insights into the development of effective species-specific natural-product-based insecticides that are more environmentally friendly than conventional insecticides.