In silico screening for identification of novel β-1,3-glucan synthase inhibitors using pharmacophore and 3D-QSAR methodologies

Meetei, Potshangbam Angamba; Rathore, R. S.; Prabhu, N. Prakash; Vindal, Vaibhav

doi:10.1186/s40064-016-2589-3

Cited by 7 publications

(3 citation statements)

References 43 publications

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“…The alpha−1,3-glucan synthase encoded by ags1, ags2, ags3 is essential for the formation of alpha−1,3-glucan [51]. fksP encoding the beta−1,3-glucan synthase participates in the synthesis of beta−1,3-glucan [52]. In our RNA-seq data, ags1, ags2, ags3 and fksP were significantly up-regulated to resist DMF destruction.…”

Section: Discussionmentioning

confidence: 65%

Dimethylformamide Inhibits Fungal Growth and Aflatoxin B1 Biosynthesis in Aspergillus flavus by Down-Regulating Glucose Metabolism and Amino Acid Biosynthesis

Pan

Peng

Jin

et al. 2020

Toxins

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Aflatoxins (AFs) are secondary metabolites produced by plant fungal pathogens infecting crops with strong carcinogenic and mutagenic properties. Dimethylformamide (DMF) is an excellent solvent widely used in biology, medicine and other fields. However, the effect and mechanism of DMF as a common organic solvent against fungal growth and AFs production are not clear. Here, we discovered that DMF had obvious inhibitory effect against A. flavus, as well as displayed complete strong capacity to combat AFs production. Hereafter, the inhibition mechanism of DMF act on AFs production was revealed by the transcriptional expression analysis of genes referred to AFs biosynthesis. With 1% DMF treatment, two positive regulatory genes of AFs biosynthetic pathway aflS and aflR were down-regulated, leading to the suppression of the structural genes in AFs cluster like aflW, aflP. These changes may be due to the suppression of VeA and the subsequent up-regulation of FluG. Exposure to DMF caused the damage of cell wall and the dysfunction of mitochondria. In particular, it is worth noting that most amino acid biosynthesis and glucose metabolism pathway were down-regulated by 1% DMF using Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Taken together, these RNA-Seq data strongly suggest that DMF inhibits fungal growth and aflatoxin B1 (AFB1) production by A. flavus via the synergistic interference of glucose metabolism, amino acid biosynthesis and oxidative phosphorylation.

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Section: Discussionmentioning

confidence: 65%

Dimethylformamide Inhibits Fungal Growth and Aflatoxin B1 Biosynthesis in Aspergillus flavus by Down-Regulating Glucose Metabolism and Amino Acid Biosynthesis

Pan

Peng

Jin

et al. 2020

Toxins

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“…To develop a pharmacophore model is an important concept in computer-aided drug design (CADD), as this method can reduce the complexity of molecular interactions between compound and target to a set of few features. This method was successfully applied in drug discovery [ 14 , 15 , 16 , 17 , 18 , 19 ] and many molecular modeling software are available among them the Molecular Operating Environment (MOE). In this study a pharmacophore model for human protein kinase CK2 was constructed on the basis of 50 indeno[1,2- b ]indoles and used to identify new hits by mining the ZINC compound database [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining

et al. 2017

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Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors. Nine common chemical features of indeno[1,2-b]indole-type CK2 inhibitors were determined using MOE software (Chemical Computing Group, Montreal, Canada). This pharmacophore model was used for database mining with the aim to identify novel scaffolds for developing new potent and selective CK2 inhibitors. Using this strategy several structures were selected by searching inside the ZINC compound database. One of the selected compounds was bikaverin (6,11-dihydroxy-3,8-dimethoxy-1-methylbenzo[b]xanthene-7,10,12-trione), a natural compound which is produced by several kinds of fungi. This compound was tested on human recombinant CK2 and turned out to be an active inhibitor with an IC50 value of 1.24 µM.

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“…Ags1 encodes a synthase that mediates the synthesis of α-1,3-glucan [ 26 ]. The enzyme β-1,3-glucan synthase, encoded by fks1 , is an essential and unique structural component of β-1,3-Glucan [ 27 ]. In the current work, ags1 and fks1 were significantly downregulated by benzenamine.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Insights into Benzenamine Effects on the Development, Aflatoxin Biosynthesis, and Virulence of Aspergillus flavus

Yang

et al. 2019

Toxins

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Aspergillus flavus is a soilborne pathogenic fungus that poses a serious public health threat due to it contamination of food with carcinogenic aflatoxins. Our previous studies have demonstrated that benzenamine displayed strong inhibitory effects on the mycelial growth of A. flavus. In this study, we systematically investigated the inhibitory effects of benzenamine on the development, aflatoxin biosynthesis, and virulence in A. flavus, as well as the underlying mechanism. The results indicated that benzenamine exhibited great capacity to combat A. flavus at a concentration of 100 µL/L, leading to significantly decreased aflatoxin accumulation and colonization capacity in maize. The transcriptional profile revealed that 3589 genes show altered mRNA levels in the A. flavus after treatment with benzenamine, including 1890 down-regulated and 1699 up-regulated genes. Most of the differentially expressed genes participated in the biosynthesis and metabolism of amino acid, purine metabolism, and protein processing in endoplasmic reticulum. Additionally, the results brought us to a suggestion that benzenamine affects the development, aflatoxin biosynthesis, and pathogenicity of A. flavus via down-regulating related genes by depressing the expression of the global regulatory factor leaA. Overall, this study indicates that benzenamine have tremendous potential to act as a fumigant against pathogenic A. flavus. Furthermore, this work offers valuable information regarding the underlying antifungal mechanism of benzenamine against A. flavus at the level of transcription, and these potential targets may be conducive in developing new strategies for preventing aflatoxin contamination.

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In silico screening for identification of novel β-1,3-glucan synthase inhibitors using pharmacophore and 3D-QSAR methodologies

Cited by 7 publications

References 43 publications

Dimethylformamide Inhibits Fungal Growth and Aflatoxin B1 Biosynthesis in Aspergillus flavus by Down-Regulating Glucose Metabolism and Amino Acid Biosynthesis

Dimethylformamide Inhibits Fungal Growth and Aflatoxin B1 Biosynthesis in Aspergillus flavus by Down-Regulating Glucose Metabolism and Amino Acid Biosynthesis

Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining

Transcriptomic Insights into Benzenamine Effects on the Development, Aflatoxin Biosynthesis, and Virulence of Aspergillus flavus

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