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

Kotaro Koiwai; Kana Morohashi; Kazue Inaba; Kana Ebihara; Hirotatsu Kojima; Takayoshi Okabe; Ryunosuke Yoshino; Takatsugu Hirokawa; Taiki Nampo; Yuuta Fujikawa; Hideshi Inoue; Fumiaki Yumoto; Toshiya Senda; Ryusuke Niwa

doi:10.1584/jpestics.D20-072

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

J Pestic Sci. 2021 Feb 20;46(1):75-87. doi: 10.1584/jpestics.D20-072.

Authors

Kotaro Koiwai¹, Kana Morohashi², Kazue Inaba^{1

2}, Kana Ebihara², Hirotatsu Kojima³, Takayoshi Okabe³, Ryunosuke Yoshino⁴, Takatsugu Hirokawa^{5

6

7}, Taiki Nampo⁸, Yuuta Fujikawa⁸, Hideshi Inoue⁸, Fumiaki Yumoto¹, Toshiya Senda^{1

9

10}, Ryusuke Niwa^{1

2

11}

Affiliations

¹ Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization, 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan.
² Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
³ Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
⁴ Graduate School of Comprehensive Human Sciences Majors of Medical Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁵ Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁶ Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁷ Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
⁸ School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
⁹ School of High Energy Accelerator Science, SOKENDAI University, 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan.
¹⁰ Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Ibaraki 305-8571, Japan.
¹¹ Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.

Abstract

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 17β-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 17β-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.

Keywords: ecdysone; ecdysteroid; glutathione S-transferase; insect growth regulator; structure–activity relationship.

© Pesticide Science Society of Japan 2021. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License (https://creativecommons.org/licenses/by-nc-nd/4.0/).