In silico screening for compounds that match the pharmacophore of omega-hexatoxin-Hv1a leads to discovery and optimization of a novel class of insecticides

Previously, scanning mutagenesis studies of the insecticidal peptide omega-hexatoxin-Hv1a identified a set of structural features used by the omega-hexatoxin-1 family to modulate insect calcium channels. These structural features were re-purposed as a 3D search term (i.e., a pharmacophore model) for mining commercially available compound databases, and screening of 1370 of the resultant candidate compounds against larvae of the mosquito Aedes aegypti and the beet armyworm Spodoptera exigua yielded insecticidal leads. One family of lead compounds, typified by a triazine core, showed inhibitory activity against voltage-gated calcium currents of cockroach DUM neurons and was optimized with guidance from SAR studies and the 3D search term. This led to characterization of a class of aryl triazines with greatly increased activity against both mosquitoes and lepidopterans. To our knowledge, discovery of such an active class of lead compounds using such a small set of pre-screened candidate compounds—selected on the basis of a pharmacophore model derived from an insecticidal venom peptide—is not precedented in the literature.

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► In silico models of the pharmacophore of an insect-selective peptide toxin were constructed.
► The pharmacophore models were used to search a database of synthetic compounds.
► The database searches identified candidate molecules that matched the pharmacophore models.
► Cheminformatic analysis led to selection and bioassay screening of 1370 candidate molecules.
► Insecticidal hits were identified, including a triazine family that was optimized by analoging.