Non-steroidal inhibitors of Drosophila melanogaster steroidogenic glutathione S-transferase Noppera-bo

Insect growth regulators (IGRs) can be developed by elucidating the molecular mechanisms of insect-specific biological events. Because insect molting, and metamorphosis are controlled by ecdysteroids, their biosynthetic pathways can serve as targets for IGR development. The glutathione S-transferase Noppera-bo (Nobo), which is conserved in dipteran and lepidopteran species, plays an essential role in ecdysteroid biosynthesis. Our previous study using 17 beta-estradiol as a molecular probe revealed that Asp113 of Drosophila melanogaster Nobo (DmNobo) is essential for its biological function. However, to develop IGRs with a greater Nobo inhibitory activity than 17 beta-estradiol, further structural information is warranted. Here, we report five novel non -steroidal DmNobo inhibitors. Analysis of crystal structures of complexes revealed that DmNobo binds these inhibitors in an Asp113-independent manner. Among amino acid residues at the substrate -recognition site, conformation of conserved Phe39 was dynamically altered upon inhibitor binding. Therefore, these inhibitors can serve as seed compounds for IGR development.

Automated summary

The development of IGRs involves elucidating the molecular mechanisms of insect-specific biological events, with insect molting and metamorphosis controlled by ecdysteroids serving as targets for IGR development. The conserved Nobo plays a crucial role in ecdysteroid biosynthesis, and novel non-steroidal DmNobo inhibitors have been identified as potential seed compounds for IGR development. Crystal structure analysis revealed dynamic alterations in amino acid residues upon inhibitor binding, indicating the potential for developing IGRs with greater Nobo inhibitory activity.