Virtual screening identifies a novel piperazine-based insect juvenile hormone agonist |
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| Authors: | Taiyo Yokoi Taku Nabe Shinri Horoiwa Ken&#x;ichiro Hayashi Sayoko Ito-Harashima Takashi Yagi Yoshiaki Nakagawa Hisashi Miyagawa |
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| Institution: | 1.Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606–8502, Japan;2.Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2–2 Yamada-oka, Suita, Osaka 565–0871, Japan;3.Department of Biology, Graduate School of Science, Osaka Prefecture University, 1–2 Gakuen-cho, Naka-ku, Sakai, Osaka 599–8570, Japan |
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| Abstract: | Juvenile hormone (JH) agonists constitute a subclass of insect growth regulators and play important roles in insect pest management. In this work, a multi-step virtual screening program was executed to find novel JH agonists. A database of 5 million purchasable compounds was sequentially processed with three computational filters: (i) shape and chemical similarity as compared to known JH-active compounds; (ii) molecular docking simulations against a Drosophila JH receptor, methoprene-tolerant; and (iii) free energy calculation of ligand–receptor binding using a modified MM/PBSA (molecular mechanics/Poisson–Boltzmann surface area) protocol. The 11 candidates that passed the three filters were evaluated in a luciferase reporter assay, leading to the identification of a hit compound that contains a piperazine ring system (EC50=870 nM). This compound is structurally dissimilar to known JH agonists and synthetically easy to access; therefore, it is a promising starting point for further structure optimization. |
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| Keywords: | juvenile hormone agonist methoprene-tolerant virtual screening molecular dynamics MM/PBSA Drosophila melanogaster |
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