Structure-Based Virtual Screening, Compound Synthesis, and Bioassay for the Design of Chitinase Inhibitors

Dong, Yawen; Jiang, Xi; Liu, Tian; Ling, Yun; Yang, Qing; Zhang, Li; He, Xiongkui

doi:10.1021/acs.jafc.8b00017

Cited by 50 publications

(49 citation statements)

References 39 publications

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“…Molecular docking is an effective way in drug structure‐based design to generate elementary predictions of the binding modes 60 . In order to verify the possible detoxification mechanism of safener to Zea mays , CSA, compound II‐1 and DKN were respectively docked with Zea mays HPPD (PDB ID: 1SP8), and the theoretical binding mode is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Fragments recombination, design, synthesis, safener activity and CoMFA model of novel substituted dichloroacetylphenyl sulfonamide derivatives

Wang

Zhao

et al. 2020

Pest Management Science

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BACKGROUND Isoxaflutole (IXF), as a kind of 4‐hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor, has been widely used in many kinds of plants. IXF can cause injury in corn including leaf and stem bleaching, plant height reduction or stunting, and reduced crop stand. Safeners are co‐applied with herbicides to protect crops without compromising weed control efficacy. With the ultimate goal of addressing Zea mays injury caused by IXF, a series of novel substituted dichloroacetylphenyl sulfonamide derivatives was designed on the basis of scaffold hopping and active substructure splicing. RESULTS A total of 35 compounds were synthesized via acylation reactions. All the compounds were characterized by infrared (IR), proton and carbon‐13 nuclear magnetic resonance (1H‐NMR and 13C‐NMR), and high‐resolution mass spectrometry (HRMS). The configuration of compound II‐1 was confirmed by single crystal X‐ray diffraction. The bioassay results showed that all the title compounds displayed remarkable protection against IXF via improved content of carotenoid. Especially compound II‐1 which possessed better glutathione transferases (GSTs) activity and carotenoid content than the contrast safener cyprosulfamide (CSA). All the satisfied parameters suggested that the Comparative Molecular Field Analysis (CoMFA) model was reliable and stable [with a cross‐validated coefficient (q2) = 0.527, r2 = 0.995, r2 pred = 0.931]. The molecular docking simulation indicated that the compound II‐1 and CSA could compete with diketonitrile (DKN) at the active site of HPPD, which is a hydrolyzed product of IXF in plants, causing the herbicide to be ineffective. CONCLUSIONS The present work revealed that the compound II‐1 deserves further attention as the candidate structure of safeners. © 2020 Society of Chemical Industry

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Section: Resultsmentioning

confidence: 99%

Fragments recombination, design, synthesis, safener activity and CoMFA model of novel substituted dichloroacetylphenyl sulfonamide derivatives

Wang

Zhao

et al. 2020

Pest Management Science

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“…Another SBVS study to identify Of ChtI inhibitors revealed that the 2-amino-6-methyl-4,5,6,7-tetrahydro-benzo-[ b ]thiophene-3-carboxylic acid ethyl ester scaffold also inhibited Of ChtI . Several derivatives were synthesized, and the most efficient compound ( 11 ) showed inhibitory activity toward Of ChtI, with a K i value of 1.5 μM.…”

Section: Development Of Small Molecules Targeting Insect Chitinasesmentioning

confidence: 99%

Development of Novel Pesticides Targeting Insect Chitinases: A Minireview and Perspective

Chen

Yang

2020

J. Agric. Food Chem.

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Chitinase (EC 3.2.1.14) is an enzyme to breakdown β-1,4-glycosidic bonds in chitin and chitooligosaccharides. The loss of chitinase enzymatic activity in insects results in severe exoskeleton defects and lethality at all developmental stages, indicating that insect chitinases can be promising pesticide targets. However, there are no pesticides known to target chitinases. This perspective will focus on the latest research progress of insect chitinases, paying special attention to crystal structures and chemical biology advances in the field. The physiological importance and unique structural features of insect chitinases may ensure the development of new pesticides through a novel acting mode.

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“…Dong et al . screened six candidate compounds from a library of 200 000 compounds using a structure‐based virtual screening approach and reported 2‐(3‐cyclopentylpropanamido)‐6‐methyl‐4,5,6,7‐tetrahydro‐benzo[ b ]thiophene‐3‐carboxylic acid propyl ester among those six candidate compounds to possess the strongest inhibitory activity [27]. However, this compound showed a binding affinity of about −8.76 to −6.96 kcal·mol −1 and it did not show any cancer cell‐killing effects.…”

Section: Discussionmentioning

confidence: 99%

A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL‐13Rα2‐mediated JNK‐AP‐1 signals

Lee

Kim

et al. 2021

Molecular Oncology

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Our previous big data analyses showed a high level of association between chitinase 3 like1 (CHI3L1) expression and lung tumor development. In the present study, we investigated whether a CHI3L1‐inhibiting chemical, 2‐({3‐[2‐(1‐cyclohexen‐1‐yl)ethyl]‐6,7‐dimethoxy‐4‐oxo‐3,4‐dihydro‐2‐quinazolinyl}sulfanyl)‐N‐(4‐ethylphenyl)butanamide (K284), could inhibit lung metastasis and studied its mechanism of action. We investigated the antitumor effect of K284 both in vitro and in vivo. K284 (0.5 mg·kg−1 body weight) significantly inhibited lung metastasis in in vivo models after injection of murine melanoma cells (B16F10) or adenocarcinomic human alveolar basal epithelial cells (A549). K284 significantly and concentration‐dependently also inhibited cancer cell proliferation and migration in the A549 and H460 lung cancer cell lines. We found that the binding of K284 to the chitin‐binding domain (CBD) of CHI3L1 prevented the binding of CHI3L1 to its receptor, interleukin‐13 receptor subunit alpha‐2 (IL‐13Rα2), thereby suppressing the CHI3L1 signal. This blocking of the CHI3L1‐IL‐13Rα2 signal caused the inhibition of c‐Jun N‐terminal kinase (JNK)‐activator protein 1 (AP‐1) signals, resulting in the prevention of lung metastasis and cancer cell growth. Our data demonstrate that K284 may serve as a potential candidate anticancer compound targeting CHI3L1.

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Structure-Based Virtual Screening, Compound Synthesis, and Bioassay for the Design of Chitinase Inhibitors

Cited by 50 publications

References 39 publications

Fragments recombination, design, synthesis, safener activity and CoMFA model of novel substituted dichloroacetylphenyl sulfonamide derivatives

Fragments recombination, design, synthesis, safener activity and CoMFA model of novel substituted dichloroacetylphenyl sulfonamide derivatives

Development of Novel Pesticides Targeting Insect Chitinases: A Minireview and Perspective

A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL‐13Rα2‐mediated JNK‐AP‐1 signals

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