Harnessing Protein-Ligand Interaction Fingerprints to Predict New Scaffolds of RIPK1 Inhibitors

Necroptosis has emerged as an exciting target in oncological, inflammatory, neurodegenerative, and autoimmune diseases, in addition to acute ischemic injuries. It is known to play a role in innate immune response, as well as in antiviral cellular response. Here we devised a concerted in silico and experimental framework to identify novel RIPK1 inhibitors, a key necroptosis factor. We propose the first in silico model for the prediction of new RIPK1 inhibitor scaffolds by combining docking and machine learning methodologies. Through the data analysis of patterns in docking results, we derived two rules, where rule #1 consisted of a four-residue signature filter, and rule #2 consisted of a six-residue similarity filter based on docking calculations. These were used in consensus with a machine learning QSAR model from data collated from ChEMBL, the literature, in patents, and from PubChem data. The models allowed for good prediction of actives of >90, 92, and 96.4% precision, respectively. As a proof-of-concept, we selected 50 compounds from the ChemBridge database, using a consensus of both molecular docking and machine learning methods, and tested them in a phenotypic necroptosis assay and a biochemical RIPK1 inhibition assay. A total of 7 of the 47 tested compounds demonstrated around 20–25% inhibition of RIPK1’s kinase activity but, more importantly, these compounds were discovered to occupy new areas of chemical space. Although no strong actives were found, they could be candidates for further optimization, particularly because they have new scaffolds. In conclusion, this screening method may prove valuable for future screening efforts as it allows for the exploration of new areas of the chemical space in a very fast and inexpensive manner, therefore providing efficient starting points amenable to further hit-optimization campaigns.     

Green Extraction Techniques as Advanced Sample Preparation Approaches in Biological,Food, and Environmental Matrices: A Review

Green extraction techniques (GreETs) emerged in the last decade as greener and sustainable alternatives to classical sample preparation procedures aiming to improve the selectivity and sensitivity of analytical methods, simultaneously reducing the deleterious side effects of classical extraction techniques (CETs) for both the operator and the environment. The implementation of improved processes that overcome the main constraints of classical methods in terms of efficiency and ability to minimize or eliminate the use and generation of harmful substances will promote more efficient use of energy and resources in close association with the principles supporting the concept of green chemistry. The current review aims to update the state of the art of some cutting-edge GreETs developed and implemented in recent years focusing on the improvement of the main analytical features, practical aspects, and relevant applications in the biological, food, and environmental fields. Approaches to improve and accelerate the extraction efficiency and to lower solvent consumption, including sorbent-based techniques, such as solid-phase microextraction (SPME) and fabric-phase sorbent extraction (FPSE), and solvent-based techniques (μQuEChERS; micro quick, easy, cheap, effective, rugged, and safe), ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE), in addition to supercritical fluid extraction (SFE) and pressurized solvent extraction (PSE), are highlighted.     

Pigment Production by Filamentous Fungi on Agro-Industrial Byproducts: an Eco-Friendly Alternative

The search for new sources of natural pigments has increased, mainly because of the toxic effects caused by synthetic dyes used in food, pharmaceutical, textile, and cosmetic industries. Fungi provide a readily available alternative source of natural pigments. In this context, the fungi Penicillium chrysogenum IFL1 and IFL2, Fusarium graminearum IFL3, Monascus purpureus NRRL 1992, and Penicillium vasconiae IFL4 were selected as pigments producers. The fungal identification was performed using ITS and part of the β-tubulin gene sequencing. Almost all fungi were able to grow and produce water-soluble pigments on agro-industrial residues, with the exception of P. vasconiae that produced pigments only on potato dextrose broth. The production of yellow pigments was predominant and the two strains of P. chrysogenum were the largest producers. In addition, the production of pigments and mycotoxins were evaluated in potato dextrose agar using TOF-MS and TOF-MS/MS. Metabolites as roquefortine C, chrysogine were found in both extracts of P. chrysogenum, as well fusarenone X, diacetoxyscirpenol, and neosolaniol in F. graminearum extract. In the M. purpureus extract, the pigments monascorubrin, rubropunctatin, and the mycotoxin citrinin were found. The crude filtrates have potential to be used in the textile industry; nevertheless, additional pigment purification is required for food and pharmaceutical applications.     

Drying of solids with irregular geometry: numerical study and application using a three-dimensional model

This article proposes a numerical solution for the diffusion equation applied to solids with arbitrary geometry using non-orthogonal structured grids for the boundary condition of the first kind. A transient three-dimensional mathematical formulation written in boundary fitted coordinates and numerical formalism to discretize the diffusion equation by using the finite volume method, including numerical analysis of the computational solution are presented. To validate the proposed solution, the results obtained in this work were compared with well-known numerical solution available in literature and good agreement was observed. In order to verify the potential of the proposed numerical solution, it was applied to describe mass transfer inside ceramic roof tiles during drying. For that, it was used experimental data of the drying kinetics at the following temperatures: 55.6; 69.7; 82.7 and 98.6 °C. An optimization technique using experimental dataset has been presented to estimation of transport properties. The obtained statistical indicators enable to conclude that the numerical solution satisfactorily describes the drying processes.     

A numerical analysis of a class of generalized Boussinesq‐type equations using continuous/discontinuous FEM

An improved class of Boussinesq systems of an arbitrary order using a wave surface elevation and velocity potential formulation is derived. Dissipative effects and wave generation due to a time‐dependent varying seabed are included. Thus, high‐order source functions are considered. For the reduction of the system order and maintenance of some dispersive characteristics of the higher‐order models, an extra O(μ²ⁿ⁺²) term (n ∈ ?) is included in the velocity potential expansion. We introduce a nonlocal continuous/discontinuous Galerkin FEM with inner penalty terms to calculate the numerical solutions of the improved fourth‐order models. The discretization of the spatial variables is made using continuous P₂ Lagrange elements. A predictor‐corrector scheme with an initialization given by an explicit Runge–Kutta method is also used for the time‐variable integration. Moreover, a CFL‐type condition is deduced for the linear problem with a constant bathymetry. To demonstrate the applicability of the model, we considered several test cases. Improved stability is achieved. Copyright © 2011 John Wiley & Sons, Ltd.     

Molecule-based kinetic modeling by Monte Carlo methods for heavy petroleum conversion

A methodology for kinetic modeling of conversion processes is presented.The proposed approach allows to overcome the lack of molecular detail of the petroleum fractions and to simulate the reactions of the process by means of a two-step procedure.In the first step,a synthetic mixture of molecules representing the feedstock is generated via a molecular reconstruction method,termed SR-REM molecular reconstruction.In the second step,a kinetic Monte Carlo method,termed stochastic simulation algorithm(SSA),is used to simulate the effect of the conversion reactions on the mixture of molecules.The resulting methodology is applied to the Athabasca vacuum residue hydrocracking.An adequate molecular representation of the vacuum residue is obtained using the SR-REM algorithm.The reaction simulations present a good agreement with the laboratory data for Athabasca vacuum residue conversion.In addition,the proposed methodology provides the molecular detail of the vacuum residue conversion throughout the reactions simulations.     

Synthesis in Water and Antimicrobial Activity of 5-Trichloromethyl-4,5-dihydroisoxazoles

Two series of 5-trichloromethylisoxazoles were synthesized from the cyclocondensation of 1,1,1-trichloro-4-methoxy-3-alken-2-ones [Cl₃CC(O)C(R²) = C(R¹)OMe, where R¹ = H, Me, Et, Pr, iso-Pr, cyclo-Pr, Bu, terc-Bu, CH₂Br, CHBr₂, CH(Me)SMe, (CH₂)₂Ph, and Ph, and R² = H; R¹ = H and R² = Me and Et; R¹ and R² = -(CH₂)₄- and -(CH₂)₅-; and R¹ = Et and Ph and R² = Me] with hydroxylamine hydrochloride through a rapid one-pot reaction in water. The 5-trichloromethyl-4,5-dihydroisoxazoles were aromatized by reaction with concentrated sulfuric acid to obtain the respective 5-trichloromethylisoxazoles. Their structures were confirmed by elemental analysis, ¹H/¹³C nuclear magnetic resonance, and electron impact mass spectroscopy. Crystal structure analysis for 5-triclhoromethyl-5-hydroxy-3-propyl-4,5-dihydroisoxazole (2d) and 5-trichloromethyl-5-hydroxy-3,4-hexamethylene-4,5-dihydroisoxazole (2o) is presented. The antimicrobial activities of the 5-trichloromethyl-4,5-dihydroisoxazole derivatives were examined using the standard twofold dilution method against Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and yeasts (Candida spp. and Cryptococcus neoformans). All of the tested 5-trichloromethyldihydroisoxazoles exhibited antibacterial and antifungal activities at the tested concentrations.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Analytical-numerical solution for turbulent jet diffusion flames of hydrogen

The hydrogen fuel seems to be a good candidate to replace the energy obtained from some fossil fuels. Therefore this work explains the process of obtaining a two-step reduced chemical kinetic mechanism for the hydrogen combustion. The development of a reduced mechanism consists in eliminating reactions that produce negligible influence on the combustion process. Moreover, for this mechanism, we obtain an analytical-numerical solution for a turbulent jet diffusion flame. To quantify the intermediate species, the mixture fraction is decomposed into three parts, each part directly related to the mass fraction of a species. The governing equations are discretized using the second order finite-difference approach and are integrated in time using the second order simplified three-step Runge-Kutta scheme. Obtained results compare favorably with data in the literature for a 50/50 % volume H ₂?N ₂ jet diffusion flame. The main advantage of this strategy is the decrease of the work needed to solve the system of governing equations, by one order of magnitude for the hydrogen.     

A simple and convenient method for synthesis of new aminonaphthoquinones derived from lawsone by catalytic multicomponent Mannich reaction

A clean, efficient and facile one-pot protocol was developed for the synthesis of a series of new aminonaphthoquinones derived from 2-hydroxy-1,4-naphthoquinone (lawsone) by three-component Mannich reaction using catalytic amount of p-TsOH in CH₃CN, at room temperature. At the present work, we improved the yield and significantly reduced the reaction time for several Mannich reactions with different amine and aromatic aldehydes using a non-expensive, mild catalyst and suitable solvent.