RESUMO
Transfer learning is a machine learning technique that works well with chemical endpoints, with several papers confirming its efficiency. Although effective, because the choice of source/assistant tasks is non-trivial, the application of this technique is severely limited by the domain knowledge of the modeller. Considering this limitation, we developed a purely data-driven approach for source task selection that abstracts the need for domain knowledge. To achieve this, we created a supervised learning setting in which transfer outcome (positive/negative) is the variable to be predicted, and a set of six transferability metrics, calculated based on information from target and source datasets, are the features for prediction. We used the ChEMBL database to generate 100,000 transfers using random pairing, and with these transfers, we trained and evaluated our transferability prediction model (TP-Model). Our TP-Model achieved a 135-fold increase in precision while achieving a sensitivity of 92%, demonstrating a clear superiority against random search. In addition, we observed that transfer learning could provide considerable performance increases when applicable, with an average Matthews Correlation Coefficient (MCC) increase of 0.19 when using a single source and an average MCC increase of 0.44 when using multiple sources.
Assuntos
Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade , Bases de Dados FactuaisRESUMO
Monoterpenes are non-polar secondary metabolites widely used by industry due to their excellent therapeutic, food-ingredient and cosmetic properties. However, their low solubility in water limits their use. In this sense, cyclodextrins (CDs) have been widely used to solve these technological challenges. Thus, this study aims to use (-)-borneol as a monoterpene model to prepare inclusion complexes between ß-CD and hydroxypropyl-ß-CD (HP-ß-CD) through different ways and characterize them in order to choose the best inclusion method to improve physicochemical properties of monoterpenes. To achieve this goal, the samples were prepared by physical mixture (PM), paste complex (PA) and freeze-drying complex (FD) and then, extensively characterized by thermal analysis, Fourier-transform infrared spectroscopy, scanning electron microscopy, size particle, X-ray diffraction and nuclear magnetic resonance. The physicochemical results showed that freeze-drying was more effective to form inclusion complexes between (-)-borneol with both CDs. This research highlights the importance of recognizing the best method to prepare inclusion complexes, including food additives as (-)-borneol, to achieve better results in food preparations.
Assuntos
Canfanos/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Varredura Diferencial de Calorimetria , Ingredientes de Alimentos , Liofilização/métodos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Monoterpenos/química , Tamanho da Partícula , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios XRESUMO
In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03µM. The 8c derivative showed the highest potency against cruzain (IC50=2.4µM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.
Assuntos
Tiazolidinas/farmacologia , Tiofenos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/toxicidade , Glicina/química , Camundongos , Simulação de Acoplamento Molecular , Octoxinol , Proteínas de Protozoários/antagonistas & inibidores , Tiazolidinas/síntese química , Tiazolidinas/toxicidade , Tiofenos/síntese química , Tiofenos/toxicidade , Tioureia/análogos & derivados , Tioureia/síntese química , Tioureia/farmacologia , Tioureia/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidadeRESUMO
Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.