Protein structure based rational design of ecdysone agonists

Holmwood, G.; Schindler, Michael

doi:10.1016/j.bmc.2009.01.008

Cited by 31 publications

(17 citation statements)

References 30 publications

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“…Mp: 174-175°C. 1 Other acrylamide analogs (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) were synthesized in a similar manner to that described for compound 2. Analytical data for the compounds are shown below.…”

Section: Thiadiazole (Step A)mentioning

confidence: 99%

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Structure–activity relationship of imidazothiadiazole analogs for the binding to the ecdysone receptor of insect cells

Yokoi¹,

Minami²,

Nakagawa³

et al. 2015

Pesticide Biochemistry and Physiology

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Diacylhydrazines are the first non-steroidal ecdysone agonists, and five compounds are used as insecticides in agriculture. After the discovery of diacylhydrazine-type compounds, numerous non-steroidal structures were reported as ecdysone agonists. Among various ecdysone agonists, imidazothiadiazoles are reported to be very potent in vitro; however, the experimental detail for the structure identification and bioassays are not stated in the paper (Holmwood and Schindler, Bioorg. Med. Chem. 17, 4064-4070, 2009). In our present study, we synthesized 18 imidazothiadiazole-type compounds and confirmed the chemical structures by spectrometric analyses. The binding activity of the synthesized compounds to the ecdysone receptor was evaluated in terms of the concentration required for 50% inhibition of [(3)H]ponasterone A incorporation [IC50 (M)] into lepidopteran (Sf-9), coleopteran (BCRL-Lepd-SL1), and dipteran (NIAS-AeAl2) cells. 6-(2-Chlorophenyl)-2-(trifluoromethyl)imidazo[2,1-b] [1,3,4]-thiadiazol-5-yl)acrylamide analogs with CONHR (secondary amide) were very potent against Sf-9 cells, but further alkylation (tertiary amide: CONR2) decreased the activity dramatically. Additionally, a primary amide analog (CONH2) was inactive. The activity also decreased 150-fold by the saturation of olefin region of the acrylamide moiety. In addition, various substituents were introduced at the 2-position of the imidazothiadiazole ring to disclose the physicochemical properties of the substituents which are important for receptor binding. The activity increased by 7500-fold with the introduction of the CF2CF2CF3 group compared to the unsubstituted compound against Sf-9 cells. Quantitative structure-activity relationship analysis for these substituents indicated that hydrophobic and electron-withdrawing groups were favorable for binding. Some of the compounds with strong receptor binding activity showed good larvicidal activity against Spodoptera litura. In contrast, the binding affinity of imidazothiadiazole analogs was low or not observed against dipteran and coleopteran cells.

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Section: Thiadiazole (Step A)mentioning

confidence: 99%

“…In 2009, Holmwood and Schindler reported that imidazole (IMD) and imidazothiadiazole (ITD)-type compounds are ecdysone agonists (Fig. 2) [9]. Although the biological activity was evaluated quantitatively in terms of pInd50 (EcR induction assay), experimental procedures and target insect species have not been described.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationship of imidazothiadiazole analogs for the binding to the ecdysone receptor of insect cells

Yokoi¹,

Minami²,

Nakagawa³

et al. 2015

Pesticide Biochemistry and Physiology

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“…This led to improvements of analytical tools for identifying additional pytoecdysones, some of which may represent interesting leads for the development of novel pesticides [125]. X-ray structures of the ligand-binding domain of EcR from various insect pests were elucidated [126] in order to identify differences in the ligand-binding pocket, providing a molecular basis for the selectivity of diacylhydrazine insecticides, while computational modelling of receptor ligand interactions was developed [127][128][129][130]. Considerable efforts were made to characterise the ligand binding properties of EcR from various insect pests [48].…”

Section: Ecdysteroid Mimicks As Pesticidesmentioning

confidence: 99%

Ecdysteroid hormone action

Spindler

Honl

Tremmel

et al. 2009

Cell. Mol. Life Sci.

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Several reviews devoted to various aspects of ecdysone research have been published during the last few years. Therefore, this article concentrates mainly on the considerable progress in ecdysone research observed recently, and will cover the results obtained during the last 2 years. The main emphasis is put on the molecular mode of ecdysteroid receptor-mediated hormone action. Two examples of interaction with other hormonal signalling pathways are described, namely crosstalk with juvenile hormone and insulin. Some selected, recently investigated examples of the multitude of hormonal responses are described. Finally, ecological aspects and some practical applications are discussed.

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“…Nakagawa et al reported a series of substituted DBHs and analyzed the relationship between the substituent properties and the inhibitory activity by QSAR methods, which revealed the strong influence of the hydrophobicity of the DBH on molting activity [15][16][17][18][19]. Holmwood et al designed imidazole-and thiadiazoloimidazole-type ecdysone agonists based on the shapes of the DBH-binding pockets [20]. Harada et al virtually screened novel nonsteroidal structures according to the binding conformation of PonA when bound to the HvEcR-LBD [21].…”

Section: Introductionmentioning

confidence: 99%

Exploration of the binding affinities between ecdysone agonists and EcR/USP by docking and MM-PB/GBSA approaches

Xie

et al. 2017

J Mol Model

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Ecdysone receptor (EcR) is a significant target in the identification of new environmentally friendly pesticides. There are two types of ecdysone agonists: steroidal ecdysone agonists and dibenzoylhydrazines (DBHs). In this study, various modeling methods (homology modeling, molecular docking, MD simulation, binding free energy calculation, and per-residue binding free energy decomposition) were utilized to study the different binding mechanisms of two types of ecdysone agonists. Our theoretical results indicated that the relative binding potencies of DBHs can be ranked sufficiently accurately using the MOE docking method. However, MM/PBSA calculations more accurately predicted the binding affinities between steroidal ecdysone agonists and EcR-LBD. To identify the key residues involved in ecdysone agonist binding, the binding free energy (ΔG ) was decomposed into the energy contributions of individual residues. The results revealed that nine residues-Ile339, Thr343, Met380, Met381, Tyr403, Tyr408, Asp419, Gln503, and Asn504-determined the binding affinities of the DBHs. Glu309, Met342, Arg383, Arg387, and Leu396 were important influences on the binding affinities of the steroidal ecdysone agonists. Graphical abstract The ecdysone receptor (EcR) is related to insect growth and has been shown to be a useful target for insecticides.

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Protein structure based rational design of ecdysone agonists

Cited by 31 publications

References 30 publications

Structure–activity relationship of imidazothiadiazole analogs for the binding to the ecdysone receptor of insect cells

Structure–activity relationship of imidazothiadiazole analogs for the binding to the ecdysone receptor of insect cells

Ecdysteroid hormone action

Exploration of the binding affinities between ecdysone agonists and EcR/USP by docking and MM-PB/GBSA approaches

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