Yokoi Taiyo, Nabe Taku, Horoiwa Shinri, Hayashi Ken'ichiro, Ito-Harashima Sayoko, Yagi Takashi, Nakagawa Yoshiaki, Miyagawa Hisashi
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
J Pestic Sci. 2021 Feb 20;46(1):68-74. doi: 10.1584/jpestics.D20-074.
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 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 (EC=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.
保幼激素（JH）激动剂是昆虫生长调节剂的一个子类，在害虫管理中发挥着重要作用。在这项工作中，执行了一个多步骤虚拟筛选程序以寻找新型JH激动剂。一个包含500万种可购买化合物的数据库依次经过三个计算过滤器处理：（i）与已知JH活性化合物相比的形状和化学相似性；（ii）针对JH受体耐甲氧普烯进行分子对接模拟；（iii）使用改进的MM/PBSA（分子力学/泊松-玻尔兹曼表面积）协议计算配体-受体结合的自由能。通过这三个过滤器的11种候选物在荧光素酶报告基因测定中进行了评估，从而鉴定出一种含有哌嗪环系统的命中化合物（EC = 870 nM）。该化合物在结构上与已知的JH激动剂不同，并且合成上易于获得；因此，它是进一步结构优化的一个有前途的起点。
