RESUMO
The Ames mutagenicity test constitutes the most frequently used assay to estimate the mutagenic potential of drug candidates. While this test employs experimental results using various strains of Salmonella typhimurium, the vast majority of the published in silico models for predicting mutagenicity do not take into account the test results of the individual experiments conducted for each strain. Instead, such QSAR models are generally trained employing overall labels (i.e., mutagenic and nonmutagenic). Recently, neural-based models combined with multitask learning strategies have yielded interesting results in different domains, given their capabilities to model multitarget functions. In this scenario, we propose a novel neural-based QSAR model to predict mutagenicity that leverages experimental results from different strains involved in the Ames test by means of a multitask learning approach. To the best of our knowledge, the modeling strategy hereby proposed has not been applied to model Ames mutagenicity previously. The results yielded by our model surpass those obtained by single-task modeling strategies, such as models that predict the overall Ames label or ensemble models built from individual strains. For reproducibility and accessibility purposes, all source code and datasets used in our experiments are publicly available.
Assuntos
Mutagênicos , Redes Neurais de Computação , Mutagênicos/toxicidade , Reprodutibilidade dos Testes , Mutagênese , Simulação por Computador , Testes de Mutagenicidade/métodosRESUMO
Alzheimer's disease is one of the most common neurodegenerative disorders in elder population. The ß-site amyloid cleavage enzyme 1 (BACE1) is the major constituent of amyloid plaques and plays a central role in this brain pathogenesis, thus it constitutes an auspicious pharmacological target for its treatment. In this paper, a QSAR model for identification of potential inhibitors of BACE1 protein is designed by using classification methods. For building this model, a database with 215 molecules collected from different sources has been assembled. This dataset contains diverse compounds with different scaffolds and physical-chemical properties, covering a wide chemical space in the drug-like range. The most distinctive aspect of the applied QSAR strategy is the combination of hybridization with backward elimination of models, which contributes to improve the quality of the final QSAR model. Another relevant step is the visual analysis of the molecular descriptors that allows guaranteeing the absence of information redundancy in the model. The QSAR model performances have been assessed by traditional metrics, and the final proposed model has low cardinality, and reaches a high percentage of chemical compounds correctly classified.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Quantitativa Estrutura-Atividade , Doença de Alzheimer/enzimologia , Simulação por Computador , Aprendizado de Máquina , Inibidores de Proteases/uso terapêuticoRESUMO
Quantitative structure-activity relationship modeling using machine learning techniques constitutes a complex computational problem, where the identification of the most informative molecular descriptors for predicting a specific target property plays a critical role. Two main general approaches can be used for this modeling procedure: feature selection and feature learning. In this paper, a performance comparative study of two state-of-art methods related to these two approaches is carried out. In particular, regression and classification models for three different issues are inferred using both methods under different experimental scenarios: two drug-like properties, such as blood-brain-barrier and human intestinal absorption, and enantiomeric excess, as a measurement of purity used for chiral substances. Beyond the contrastive analysis of feature selection and feature learning methods as competitive approaches, the hybridization of these strategies is also evaluated based on previous results obtained in material sciences. From the experimental results, it can be concluded that there is not a clear winner between both approaches because the performance depends on the characteristics of the compound databases used for modeling. Nevertheless, in several cases, it was observed that the accuracy of the models can be improved by combining both approaches when the molecular descriptor sets provided by feature selection and feature learning contain complementary information.
Assuntos
Descoberta de Drogas , Aprendizado de Máquina , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Algoritmos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Fenômenos Químicos , Descoberta de Drogas/métodos , Humanos , Absorção Intestinal/efeitos dos fármacos , SoftwareRESUMO
Nitric oxide-releasing alpha-tocopherol mimetics with LDL-protective activity were designed to maintain the tocopherol substructure necessary for its biochemical recognition by alpha-tocopherol transfer protein. In order to study the molecular interactions to alpha-TTP, theoretical binding studies by means of docking techniques and experimental binding assays, using a fluorescent probe, were performed. Furoxanyl-tocopherol-hybrid analogs 7 and 9 have the best ability to bind to alpha-TTP suggesting that they could be incorporated to LDL in vivo to further release nitric oxide and prevent oxidative modifications.
Assuntos
Antioxidantes/metabolismo , Doadores de Óxido Nítrico/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico/metabolismo , Tocoferóis/metabolismo , Vitamina E/metabolismo , alfa-Tocoferol , Substituição de Aminoácidos , LDL-Colesterol/química , LDL-Colesterol/metabolismo , Humanos , Dados de Sequência Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
New benzofuroxans were developed and studied as antiproliferative Trypanosoma cruzi agents. Compounds displayed remarkable in vitro activities against different strains, Tulahuen 2, CL Brener and Y. Its unspecific cytotoxicity was evaluated using human macrophages being not toxic at a concentration at least 8 times, and until 250 times, that of its T. cruzi IC50. Some biochemical pathways were studied, namely parasite respiration, cysteinyl active site enzymes and reaction with glutathione, as target for the mechanism of action. Not only T. cruzi respiration but also Cruzipain or trypanothione reductase were not affected, however the most active derivatives, the vinylsulfinyl- and vinylsulfonyl-containing benzofuroxans, react with glutathione in a redox pathway. Furthermore, the compounds showed good in vivo activities when they were studied in an acute murine model of Chagas' disease. The compounds were able to reduce the parasite loads of animals with fully established T. cruzi infections.
Assuntos
Benzoxazóis/síntese química , Doença de Chagas/tratamento farmacológico , Sulfonas/síntese química , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Compostos de Vinila/síntese química , Animais , Anticorpos Antiprotozoários/sangue , Benzoxazóis/farmacologia , Benzoxazóis/toxicidade , Linhagem Celular , Cisteína Endopeptidases/metabolismo , Feminino , Glutationa/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Modelos Moleculares , NADH NADPH Oxirredutases/metabolismo , Oxirredução , Consumo de Oxigênio/efeitos dos fármacos , Proteínas de Protozoários , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Tripanossomicidas/farmacologia , Tripanossomicidas/toxicidade , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/fisiologia , Compostos de Vinila/química , Compostos de Vinila/farmacologiaRESUMO
Se realizó un estudio prospectivo de 40 pacientes con úlcera duodenal infectados con Helicobacter pylori (histología y prueba de ureasa). Se trataron con 20 mg diarios de omeprazol durante 28 d; el grupo A (20 pacientes) recibió terapia corta con 500 mg de azitromicina 2 veces al día por 3 d y tinidazol 2g dosis única; el grupo B (20 pacientes), 500 mg de metronidazol 3 veces al día y 500 mg de tetraciclina 4 veces al día, ambos durante 7 d. Se investigó la infección y cicatrización de la úlcera después de mes y medio de concluido el tratamiento, mediante las mismas pruebas usadas para la inclusión del paciente en este trabajo y se tuvo en cuenta, como criterio de erradicación, la negatividad de las dos. La tasa de erradicación del grupo A (80 %) fue superior a la del grupo B (70 %). Hubo evolución clínica satisfactoria en los grupos, se obtuvo rápida mejoría de los síntomas en todos los pacientes del grupo A, sin reportarse efectos colaterales; en el grupo B, 9 pacientes refirieron como efectos secundarios más frecuentes, náuseas y sabor metálico. La cicatrización de la lesión fue del 90 % en cada grupo, se demostró fracaso en la erradicación en 2 pacientes de cada grupo con úlcera. La asociación del omeprazol y terapia corta con azitromicina y tinidazol ofrece ventajas frente al uso de este con metronidazol y tetraciclina por presentar mayor tasa de erradicación, cómoda posología y sin efectos colaterales reportados en este ensayo.
A prospective study of 40 patients with duodenal ulcer infected with Helicobacter pylori (histology and urease test) was conducted. They were treated with 20 daily mg of omeprazole during 28 days. Group A (20 patients) received short therapy with 500 mg of azithromycin twice a day for 3 days and a unique dose of tinidazole 2g. Group B (20 patients) was administered 500 mg of metronidazole 3 times a day and 500 mg of tetracycline 4 times a day, both during 7 days. The infection and healing of the ulcer was investigated a month and a half after concluding the treatment by using the same tests applied for the inclusion of the patient in this study. The negativity of both was taken into account as an eradication criterion. The eradication rate of group A (80 %) was higher than that of group B (70 %). A satisfactory clinical evolution was observed in the groups. A rapid improvement of the symptoms was reported in all patients from group A, and there were no side effects. In group B, 9 patients referred to nausea and metallic taste as the most common side effects. The healing of the injury was 90 % in each group. The eradication failed in 2 patients with ulcer from each group. The association of omeprazole and short therapy with azithromycin and tinidazole offers advantages over the use of omeprazole with metronidazole and tetracycline for presenting a higher eradication rate, convenient posology and no side effects.
RESUMO
Se hace una exposición del valor de la endoscopia digestiva en el diagnóstico y tratamiento del cáncer, tanto del tracto gastrointestinal como de los órganos contenidos en la cavidad abdominal y las posibilidades que ésta brinda mediante la toma de citología y biopsia, para establecer un diagnóstico de certeza que facilite la conducta terapéutica posterior