RESUMO
The catalytic performance of modified hydroxyapatite nanoparticles, Ca10-xFex-yWy(PO4)6(OH)2, was applied for the degradation of methylene blue (MB), fast green FCF (FG) and norfloxacin (NOR). XPS analysis pointed to the successful partial replacement of Ca by Fe. Under photo-electro-Fenton process, the catalyst Ca4FeII1·92W0·08FeIII4(PO4)6(OH)2 was combined with UVC radiation and electrogenerated H2O2 in a Printex L6 carbon-based gas diffusion electrode. The application of only 10 mA cm-2 resulted in 100% discoloration of MB and FG dyes in 50 min of treatment at pH 2.5, 7.0 and 9.0. The proposed treatment mechanism yielded maximum TOC removal of â¼80% and high mineralization current efficiency of â¼64%. Complete degradation of NOR was obtained in 40 min, and high mineralization of â¼86% was recorded after 240 min of treatment. Responses obtained from LC-ESI-MS/MS are in line with the theoretical Fukui indices and the ECOSAR data. The study enabled us to predict the main degradation route and the acute and chronic toxicity of the by-products formed during the contaminants degradation.
Assuntos
Eletrodos , Peróxido de Hidrogênio , Ferro , Azul de Metileno , Nanopartículas , Poluentes Químicos da Água , Catálise , Peróxido de Hidrogênio/química , Ferro/química , Azul de Metileno/química , Nanopartículas/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/análise , Norfloxacino/química , Durapatita/química , Corantes/química , Processos Fotoquímicos , Raios UltravioletaRESUMO
Electrocatalysis holds the key to the decentralized production of hydrogen peroxide via the two-electron oxygen reduction reaction (ORR, O2g+2H++e-âH2O2aq). However, cost-effective, active, and selective catalysts are still sought after. While density functional theory (DFT) has already led to the discovery of various enhanced catalysts, it has a severe yet often unnoticed drawback: the ill description of O2 and H2O2. Here, we analyze the impact of the errors in those two species on the most widespread activity plots in the literature, namely free-energy diagrams and Sabatier-type volcano plots. Uncorrected or partially corrected gas-phase energies lead to appreciably different activity plots that may provide inaccurate predictions. Indeed, we show for a variety of electrocatalysts that only when the errors in O2 and H2O2 are corrected can DFT mimic the experiments. In sum, this work provides concrete guidelines to avoid a common pitfall of computational models for electrocatalytic hydrogen peroxide production.
RESUMO
A key step in the biosynthesis of numerous polyketides is the stereospecific formation of a spiroacetal (spiroketal). We report here that spiroacetal formation in the biosynthesis of the macrocyclic polyketides ossamycin and oligomycin involves catalysis by a novel spiroacetal cyclase. OssO from the ossamycin biosynthetic gene cluster (BGC) is homologous to OlmO, the product of an unannotated gene from the oligomycin BGC. The deletion of olmO abolished oligomycin production and led to the isolation of oligomycin-like metabolites lacking the spiroacetal structure. Purified OlmO catalyzed complete conversion of the major metabolite into oligomycin C. Crystal structures of OssO and OlmO reveal an unusual 10-strand ß-barrel. Three conserved polar residues are clustered together in the ß-barrel cavity, and site-specific mutation of any of these residues either abolished or substantially diminished OlmO activity, supporting a role for general acid/general base catalysis in spiroacetal formation.
Assuntos
Policetídeos , Antibacterianos , Catálise , Família Multigênica , Oligomicinas , Policetídeos/química , Metabolismo SecundárioRESUMO
Bis(2-ethylhexyl) phthalate (DEHP) has been widely used for the production of plastics, and the compound has also been found to act as endocrine disruptor. Exposure to DEHP has been found to cause several hormonal problems, including decreased fertility. Due to the environmental and health risks posed by the use of DEHP, the present study employed molecular docking, molecular dynamics, and free energy analyses (MM-GBSA, MM-PBSA, and SIE) aiming at evaluating the action of DEHP and that of two other compounds (ATEC and DL9TH), tested as potential DEHP substitutes, on two hormone receptors (sex hormone-binding globulin - SHBG - and progesterone receptor - PR). The results obtained showed that ATEC may be a good substitute for DEHP in the production of plastics, such as PVC, considering that the compound recorded the greatest free energy values with respect to binding with SHBG (-31.36 kcal/mol obtained from MM-GBSA; -20.28 kcal/mol for MM-PBSA, and -7.40 for SIE) and PR (-36.40 kcal/mol for MM-GBSA; -27.00 kcal/mol for MM-PBSA, and -8.51 kcal/mol for SIE) - this shows that ATEC presented the least activity in the two hormone receptors. The findings of this study provide relevant insights on potential substitutes for DEHP and help shed light on the action of these new efficient substances, which have similar properties to DEHP (ATEC and DL9TH) yet do not act as endocrine disruptors.Communicated by Ramaswamy H. Sarma.
Assuntos
Dietilexilftalato , Disruptores Endócrinos , Dietilexilftalato/química , Plastificantes/química , Plastificantes/metabolismo , Disruptores Endócrinos/química , Simulação de Acoplamento Molecular , Plásticos , HormôniosRESUMO
BACKGROUND: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics. OBJECTIVE: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors. METHODS: Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase. RESULTS: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k). CONCLUSION: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.
Assuntos
Flavonoides/síntese química , Flavonoides/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Activin-like kinase 5 (ALK-5) is involved in the physiopathology of several conditions, such as pancreatic carcinoma, cervical cancer and liver hepatoma. Cellular events that are landmarks of tumorigenesis, such as loss of cell polarity and acquisition of motile properties and mesenchymal phenotype, are associated to deregulated ALK-5 signaling. ALK-5 inhibitors, such as SB505154, GW6604, SD208, and LY2157299, have recently been reported to inhibit ALK-5 autophosphorylation and induce the transcription of matrix genes. Due to their ability to impair cell migration, invasion and metastasis, ALK-5 inhibitors have been explored as worthwhile hits as anticancer agents. This work reports the development of a structure-based virtual screening (SBVS) protocol aimed to prospect promising hits for further studies as novel ALK-5 inhibitors. From a lead-like subset of purchasable compounds, five molecules were identified as putative ALK-5 inhibitors. In addition, molecular dynamics and binding free energy calculations combined with pharmacokinetics and toxicity profiling demonstrated the suitability of these compounds to be further investigated as novel ALK-5 inhibitors.
Assuntos
Antineoplásicos/química , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Sítios de Ligação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/isolamento & purificação , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Quinolinas/química , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/ultraestrutura , Interface Usuário-ComputadorRESUMO
In this work, a group of α-keto-based inhibitors of the cruzain enzyme with anti-chagas activity was selected for a three-dimensional quantitative structure-activity relationship study (3D-QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q2 and r2 )for the models were, respectively, 0.910 and 0.997 (CoMFA) and 0.913 and 0.992 (CoMSIA). In addition, external validation for the models using a test group revealed r2pred = 0.728 (CoMFA) and 0.971 (CoMSIA). The most relevant aspect in this study was the generation of molecular fields in both favorable and unfavorable regions based on the models developed. These fields are important to interpret modifications necessary to enhance the biological activities of the inhibitors. This analysis was restricted considering the inhibitors in a fixed conformation, not interacting with their target, the cruzain enzyme. Then, MD was employed taking into account important variables such as time and temperature. MD helped describe the behavior of the inhibitors and their properties showed similar results as those generated by QSAR-3D study.
Assuntos
Proteínas de Protozoários/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Sítios de Ligação , Domínio Catalítico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/patologia , Cisteína Endopeptidases/metabolismo , Humanos , Análise dos Mínimos Quadrados , Simulação de Dinâmica Molecular , Proteínas de Protozoários/metabolismoRESUMO
Activin Receptor-Like Kinase 5 (ALK-5) is related to some types of cancer, such as breast, lung, and pancreas. In this study, we have used molecular docking, molecular dynamics simulations, and free energy calculations in order to explore key interactions between ALK-5 and six bioactive ligands with different ranges of biological activity. The motivation of this work is the lack of crystal structure for inhibitor-protein complexes for this set of ligands. The understanding of the molecular structure and the protein-ligand interaction could give support for the development of new drugs against cancer. The results show that the calculated binding free energy using MM-GBSA, MM-PBSA, and SIE is correlated with experimental data with r2 = 0.88, 0.80, and 0.94, respectively, which indicates that the calculated binding free energy is in excellent agreement with experimental data. In addition, the results demonstrate that H bonds with Lys232, Glu245, Tyr249, His283, Asp351, and one structural water molecule play an important role for the inhibition of ALK-5. Overall, we discussed the main interactions between ALK-5 and six inhibitors that may be used as starting points for designing new molecules to the treatment of cancer.
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Antineoplásicos/química , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Piridinas/química , Quinazolinas/química , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Antineoplásicos/síntese química , Sítios de Ligação , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Ligação de Hidrogênio , Cinética , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Piridinas/síntese química , Quinazolinas/síntese química , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Cancer cells can expand to other parts of body through blood system and nodes from a mechanism known as metastasis. Due to the large annual growth of cancer cases, various biological targets have been studied and related to this disorder. A very interesting target related to cancer is human epidermal growth factor receptor 2 (HER2). In this study, we analyzed the main intermolecular interactions between a drug used in the cancer treatment (5-fluorouracil) and HER2. Molecular modeling methods were also employed to assess the molecular structure, spectroscopic properties (FTIR and UV-Vis), NBO, QTAIM and HOMO-LUMO energies of 5-FU. From the docking simulations it was possible to analyze the interactions that occur between some residues in the binding site of HER2 and 5-FU. To validate the choice of basis set that was used in the NBO and QTAIM analyses, theoretical calculations were performed to obtain FT-IR and UV/Vis spectra, and the theoretical results are consistent with the experimental data, showing that the basis set chosen is suitable. For the maximum λ from the theoretical calculation (254.89nm) of UV/Vis, the electronic transition from HOMO to LUMO occurs at 4.89eV. From NBO analyses, we observed interactions between Asp863 and 5-FU, i.e. the orbitals with high transfer of electrons are LP O15 (donor NBO) and BD* (π) N1-H10 (acceptor NBO), being that the value of this interaction is 7.72kcal/mol. Results from QTAIM indicate one main intermolecular H bond, which is necessary to stabilize the complex formed between the ligands and the biological target. Therefore, this study allowed a careful evaluation on the main structural, spectroscopic and electronic properties involved in the interaction between 5-FU and HER2, an important biological complex related to the cancer treatment.
Assuntos
Antineoplásicos/análise , Antineoplásicos/química , Fluoruracila/análise , Fluoruracila/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Simulação de Acoplamento Molecular , Espectrofotometria UltravioletaRESUMO
Studies have showed that there are many biological targets related to the cancer treatment, for example, TGF type I receptor (TGF-ßRI or ALK5). The ALK5 inhibition is a strategy to treat some types of cancer, such as breast, lung, and pancreas. Here, we performed CoMFA and CoMSIA studies for 70 ligands with ALK5 inhibition. The internal validation for both models (q(2)LOO = 0.887 and 0.822, respectively) showed their robustness, while the external validations showed their predictive power (CoMFA: r(2)test = 0.998; CoMSIA: r(2)test = 0.975). After all validations, CoMFA and CoMSIA maps indicated physicochemical evidences on the main factors involved in the interaction between bioactive ligands and ALK5. Therefore, these results suggest molecular modifications to design new ALK5 inhibitors.