Validation of Insect Dopa Decarboxylase as a Potential Insecticide Target and Discovery of Selective Lead Compounds

Dopa decarboxylase (DDC) is a key rate-limiting enzyme involved in cuticle tanning in insects, catalyzing the conversion of l-dopa to dopamine. Given its essential role in insect survival, DDC represents a potential target for pest control. In this study, we recombinantly expressed and characterized DDC from <i>Drosophila melanogaster</i> and developed a structural model for virtual screening. Quercetin (Que), the first identified inhibitor of insect DDC, was found to have an IC₅₀ value of 9.43 μM. Notably, Que displayed much lower inhibitory activity against human DDC, with an IC₅₀ value of 29.56 μM. Sequence-structure comparisons and molecular docking revealed several amino acid differences in the catalytic loop (L330, N326, V327, and D335) that may account for the distinct substrate specificity between insect and mammalian DDCs, as well as the differential inhibitor sensitivities. Bioassays demonstrated that Que exhibited significant insecticidal activity against the lepidopteran pest <i>Plutella xylostella</i> and the orthopteran pest <i>Locusta migratoria</i>. This study not only reinforces the potential of targeting insect DDC for insecticide development but also identifies a promising lead scaffold for further insecticide design.