In vitro screening and chemometrics analysis on a series of azole derivatives with fungicide activity against moniliophthora perniciosa

Mota, Sabrina G. R.; Barros, Tânia Fraga; Castilho, Marcelo Santos

doi:10.1590/s0103-50532010000300017

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…Compounds with increased MGMT inhibitory activities were tended to have high dipole moment (JGI4 values). The importance of charge transfer has already been reported in other study [ 26 ]. SpPosA_B(p) means normalized spectral positive sum from Burden matrix weighted by polarizability, is another important variable positively correlates with the increased MGMT inhibition of base analogs.…”

Section: Resultssupporting

confidence: 65%

In Silico Prediction of O6-Methylguanine-DNA Methyltransferase Inhibitory Potency of Base Analogs with QSAR and Machine Learning Methods

et al. 2018

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O6-methylguanine-DNA methyltransferase (MGMT), a unique DNA repair enzyme, can confer resistance to DNA anticancer alkylating agents that modify the O6-position of guanine. Thus, inhibition of MGMT activity in tumors has a great interest for cancer researchers because it can significantly improve the anticancer efficacy of such alkylating agents. In this study, we performed a quantitative structure activity relationship (QSAR) and classification study based on a total of 134 base analogs related to their ED50 values (50% inhibitory concentration) against MGMT. Molecular information of all compounds were described by quantum chemical descriptors and Dragon descriptors. Genetic algorithm (GA) and multiple linear regression (MLR) analysis were combined to develop QSAR models. Classification models were generated by seven machine-learning methods based on six types of molecular fingerprints. Performances of all developed models were assessed by internal and external validation techniques. The best QSAR model was obtained with Q2Loo = 0.83, R2 = 0.87, Q2ext = 0.67, and R2ext = 0.69 based on 84 compounds. The results from QSAR studies indicated topological charge indices, polarizability, ionization potential (IP), and number of primary aromatic amines are main contributors for MGMT inhibition of base analogs. For classification studies, the accuracies of 10-fold cross-validation ranged from 0.750 to 0.885 for top ten models. The range of accuracy for the external test set ranged from 0.800 to 0.880 except for PubChem-Tree model, suggesting a satisfactory predictive ability. Three models (Ext-SVM, Ext-Tree and Graph-RF) showed high and reliable predictive accuracy for both training and external test sets. In addition, several representative substructures for characterizing MGMT inhibitors were identified by information gain and substructure frequency analysis method. Our studies might be useful for further study to design and rapidly identify potential MGMT inhibitors.

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Section: Resultssupporting

confidence: 65%

In Silico Prediction of O6-Methylguanine-DNA Methyltransferase Inhibitory Potency of Base Analogs with QSAR and Machine Learning Methods

et al. 2018

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“…The action of azole-group antifungals has created new perspectives for controlling witches’ broom in cocoa trees and has highlighted the importance of analyzing ergosterol biosynthesis in M. perniciosa in order to develop specific inhibitors of this pathway ( McQuilken and Rudgard, 1988 ; Mota et al , 2010 ). To accomplish this, it is essential to study the development of the disease from molecular and biochemical perspectives.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the ergosterol biosynthesis pathway cloning, molecular characterization and phylogeny of lanosterol 14α-demethylase (ERG11) gene of Moniliophthora perniciosa

et al. 2014

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The phytopathogenic fungus Moniliophthora perniciosa (Stahel) Aime & Philips-Mora, causal agent of witches’ broom disease of cocoa, causes countless damage to cocoa production in Brazil. Molecular studies have attempted to identify genes that play important roles in fungal survival and virulence. In this study, sequences deposited in the M. perniciosa Genome Sequencing Project database were analyzed to identify potential biological targets. For the first time, the ergosterol biosynthetic pathway in M. perniciosa was studied and the lanosterol 14α-demethylase gene (ERG11) that encodes the main enzyme of this pathway and is a target for fungicides was cloned, characterized molecularly and its phylogeny analyzed. ERG11 genomic DNA and cDNA were characterized and sequence analysis of the ERG11 protein identified highly conserved domains typical of this enzyme, such as SRS1, SRS4, EXXR and the heme-binding region (HBR). Comparison of the protein sequences and phylogenetic analysis revealed that the M. perniciosa enzyme was most closely related to that of Coprinopsis cinerea.

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“…Também fungicidas com ação sistêmica, como estrobirulinas, triazóis e benzimidazóis foram testados e se mostraram efetivos em reduzir a germinação de esporos, esporulação e crescimento micelial do fungo in vitro e em casa de vegetação, e em alguns casos também sob condições de campo. No entanto, nunca houve adoção em escala pelos produtores de cacau por inconsistências quanto a viabilidade técnica e econômica (Albuquerque et al, 2005;Mota et al, 2010).…”

Section: O Patossistema M Perniciosa X T Cacaounclassified

Análise da capacidade de silenciamento gênico de Moniliophthora perniciosa como método de controle

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The Basidiomycete fungus Moniliophthora perniciosa is the causal agent of the disease known as "witch's broom disease", which affects cacao tree (Theobroma cacao) and is one of the main detractors of the productivity of this crop in Brazil and worldwide. The damage to cacao trees resulting from infection by this plant pathogen includes fruit rot and induction of lateral shoots in the infected branches, resulting in general weakening of the plants. Control methods of this disease, such as genetic resistance, phytosanitary pruning and chemical control have been shown to be palliative measures. Given the peculiarities of this pathosystem, one of the envisioned alternatives is the development of biologically active compounds on essential metabolic pathways capable of reducing the damage caused by the disease. In the biotrophic phase of M. perniciosa, it has been found that the alternative electron transfer pathway played by the enzyme alternative mitochondrial oxidase (AOX) is important for ATP production and fungicide tolerance. Recently, it was shown that in vitro and in vivo inhibiton of this enzyme reduced the viability of M. perniciosa spores. In this work, a new in vivo approach is purposed for the evaluation of AOX synthetic inhibitor to assess its efficacy against M. perniciosa in the tomato model 'Micro-Tom' (MT), sourced by roots via nutrient solution. On the other hand, understanding the mechanisms of phytopathogenic fungi infection paves the way for new control strategies. Recent reports in other pathosystems suggest that, in addition to effector proteins, pathogens employ small RNAs (sRNA) for direct manipulation of the plant defense system. Hosts expressing double-stranded RNA corresponding to target genes of the pathogen, including filamentous fungi, have been shown to generate small interfering RNAs (siRNA) that lead to the silencing of these target genes, in an approach named Host Induced Gene Silencing (HIGS). This project aimed to confirm the presence of genetic machinery for the production and processing of small RNAs (sRNA) and the RNA interference mechanism in the M. perniciosa genome. In addition, the 'Micro-Tom' (MT) model tomato was genetically transformed to express one of the key components of this mechanism (Dicers enzymes) to understand its role in the pathogenicity of M. perniciosa in future studies. As a result, alternative oxidase inhibitor (AOX) '7j-41' preventively administered to inoculation of M. perniciosa basidiospores was effective in reducing the severity of infection and protecting plant biomass from the deleterious effects of the pathogen. M. perniciosa has in its genome genes participating in the canonical gene silencing pathway described in fungi, including three Dicers (DCL), 10 Argonauts (AGO), and seven RNA-dependent RNA polymerase (RdRPs). These genes were mainly expressed in the monocariotic, dicariotic, primordial and basidioma mycelium phases, suggesting importance in several stages of plant-pathogen interaction. Transgenic 'Micro-Tom' tomato plants have been success...

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In vitro screening and chemometrics analysis on a series of azole derivatives with fungicide activity against moniliophthora perniciosa

Cited by 7 publications

References 21 publications

In Silico Prediction of O6-Methylguanine-DNA Methyltransferase Inhibitory Potency of Base Analogs with QSAR and Machine Learning Methods

In Silico Prediction of O6-Methylguanine-DNA Methyltransferase Inhibitory Potency of Base Analogs with QSAR and Machine Learning Methods

Analysis of the ergosterol biosynthesis pathway cloning, molecular characterization and phylogeny of lanosterol 14α-demethylase (ERG11) gene of Moniliophthora perniciosa

Análise da capacidade de silenciamento gênico de Moniliophthora perniciosa como método de controle

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