Virtual screening and activity evaluation of novel ecdysone analogues targeting overlapping binding pockets in Lepidoptera ecdysone receptor

IF 4 1区 农林科学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yanjiao Feng , Jialin Cui , Hongyan Wang , Qinyan Tan , Shangzhong Liu , Libing Liu , Li Zhang
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Abstract

The ecdysone receptor (EcR/USP) plays a vital role in regulating molting and metamorphosis in insects, rendering it an attractive green target for developing novel insect growth regulators (IGRs). In this study, the ligand pharmacophore model S1&S2 and the Combine active pockets were constructed on the basis of the two different ligand-binding pockets of Lepidoptera EcR. A multi-level virtual screening of the SPECS database was performed, using pesticide-likeness rule and molecular docking, to obtain 13 screening compounds. Then, a novel experimental method was established to evaluate Plutella xylostella EcR/USP-LBD binding to ligand molecules using the Surface Plasmon Resonance (SPR) technique. The binding assays demonstrated that compounds VS-13, VS-16, VS-17, VS-18, and VS-19 exhibited comparable or superior efficacy to the commercial insecticide methoxyfenozide. Notably, VS-13 showed the highest binding activity, with a Kd of 0.2 ± 0.03 μM, similar to Ponesterone A (PonA, Kd = 0.1 ± 0.01 μM). Furthermore, molecular docking studies revealed that, in addition to three important residues (Asn503, Tyr407, and Thr342), Trp525 and Met379 are also key residues in stable the ligand-receptor interactions. These findings provide an effective strategy to design and discovery novel non-ecdysteroid analogs targeting lepidopteran insects.

Abstract Image

针对鳞翅目蜕皮激素受体重叠结合袋的新型蜕皮激素类似物的虚拟筛选及活性评价
蜕皮激素受体(ecdyone receptor, EcR/USP)在昆虫的蜕皮和变态发育中起着重要的调节作用,是开发新型昆虫生长调节剂(IGRs)的一个有吸引力的绿色靶点。本研究以鳞翅目EcR的两种不同的配体结合袋为基础,构建了配体药效团模型S1&;S2和Combine活性袋。利用农药相似规则和分子对接对SPECS数据库进行多级虚拟筛选,得到13个筛选化合物。然后,建立了一种利用表面等离子体共振(SPR)技术评价小菜蛾EcR/USP-LBD与配体分子结合的实验方法。结合实验表明,化合物VS-13、VS-16、VS-17、VS-18和VS-19的药效与市售杀虫剂甲氧虫酰肼相当或优于甲氧虫酰肼。其中VS-13的结合活性最高,Kd为0.2±0.03 μM,与Ponesterone a (PonA, Kd = 0.1±0.01 μM)相似。此外,分子对接研究发现,除了Asn503、Tyr407和Thr342三个重要残基外,Trp525和Met379也是稳定配体-受体相互作用的关键残基。这些发现为设计和发现针对鳞翅目昆虫的新型非表皮甾体类似物提供了有效的策略。
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来源期刊
CiteScore
7.00
自引率
8.50%
发文量
238
审稿时长
4.2 months
期刊介绍: Pesticide Biochemistry and Physiology publishes original scientific articles pertaining to the mode of action of plant protection agents such as insecticides, fungicides, herbicides, and similar compounds, including nonlethal pest control agents, biosynthesis of pheromones, hormones, and plant resistance agents. Manuscripts may include a biochemical, physiological, or molecular study for an understanding of comparative toxicology or selective toxicity of both target and nontarget organisms. Particular interest will be given to studies on the molecular biology of pest control, toxicology, and pesticide resistance. Research Areas Emphasized Include the Biochemistry and Physiology of: • Comparative toxicity • Mode of action • Pathophysiology • Plant growth regulators • Resistance • Other effects of pesticides on both parasites and hosts.
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