Binding Ensembles of p53-MDM2 Peptide Inhibitors by Combining Bayesian Inference and Atomistic Simulations

Designing peptide inhibitors of the p53-MDM2 interaction against cancer is of wide interest. Computational modeling and virtual screening are a well established step in the rational design of small molecules. But they face challenges for binding flexible peptide molecules that fold upon binding. We look at the ability of five different peptides, three of which are intrinsically disordered, to bind to MDM2 with a new Bayesian inference approach (MELD × MD). The method is able to capture the folding upon binding mechanism and differentiate binding preferences between the five peptides. Processing the ensembles with statistical mechanics tools depicts the most likely bound conformations and hints at differences in the binding mechanism. Finally, the study shows the importance of capturing two driving forces to binding in this system: the ability of peptides to adopt bound conformations (ΔGconformation) and the interaction between interface residues (ΔGinteraction).     

Practical Synthesis of 2-Iodosobenzoic Acid (IBA) without Contamination by Hazardous 2-Iodoxybenzoic Acid (IBX) under Mild Conditions

We report a convenient and practical method for the preparation of nonexplosive cyclic hypervalent iodine(III) oxidants as efficient organocatalysts and reagents for various reactions using Oxone^® in aqueous solution under mild conditions at room temperature. The thus obtained 2-iodosobenzoic acids (IBAs) could be used as precursors of other cyclic organoiodine(III) derivatives by the solvolytic derivatization of the hydroxy group under mild conditions of 80 °C or lower temperature. These sequential procedures are highly reliable to selectively afford cyclic hypervalent iodine compounds in excellent yields without contamination by hazardous pentavalent iodine(III) compound.     

Terroir Effect on the Phenolic Composition and Chromatic Characteristics of Mencía/Jaen Monovarietal Wines: Bierzo D.O. (Spain) and Dão D.O. (Portugal)

‘Mencía’/‘Jaen’ it’s an important red grape variety, exclusive of the Iberian Peninsula, used in wine production namely in Bierzo D.O. and Dão D.O., respectively. This work evaluates the effect of the two different “terroirs” on the phenolic composition and chromatic characteristics of ‘Mencía’/‘Jaen’ monovarietal wines produced at an industrial scale in the same vintage. Using Principal Component Analysis (PCA), Partial Least Squares-Discrimination Analysis (PLS-DA), and Orthogonal PLS-DA (OPLS-DA) it was found that peonidin-3-coumaroylglucoside, petunidin-3-glucoside, malvidin-3-coumaroylglucoside, peonidin-3-glucoside, malvidin-3-acetylglucoside, malvidin-3-glucoside, and ferulic acid were the phenolic compounds with the highest differences between the two regions. PLS regression allowed to correlate the differences in lightness (L*) and redness (a*) of wines from ‘Jaen’ and ‘Mencía’ to differences in colored anthocyanins, polymeric pigments, total pigments, total anthocyanins, cyanidin-3-acetylglucoside, delphinidin-3-acetylglucoside, delphinidin-3-glucoside, peonidin-3-coumaroylglucoside, petunidin-3-glucoside and malvidin-3-glucoside in wines, and the colorless ferulic, caffeic, and coutaric acids, and ethyl caffeate. The wines a* values were more affected by colored anthocyanins, ferulic acid, total anthocyanins, delphinidin-3-acetylglucoside, delphinidin-3-glucoside and petunidin-3-acetylglucoside, and catechin. The positive influence of ferulic acid in the a* values and ferulic, caffeic, coutaric acids, and ethyl caffeate on the L* values can be due to the co-pigmentation phenomena. The higher dryness and lower temperatures during the September nights in this vintage might explain the differences observed in the anthocyanin content and chromatic characteristics of the wines.     

Evolution of Physicochemical Parameters during the Thermal-Based Production of Água-mel,a Traditional Portuguese Honey-Related Food Product

The purpose of this work was to investigate the physicochemical changes occurring during the thermal-based production of água-mel, a traditional Portuguese honey-related food product. The refractive index, color parameters (hue angle, H°; chroma, C*), and the content of total reducing sugars, glucose, fructose, total brown pigments, and 5-hydroxymethylfurfural were monitored along the entire production process, and their evolution was kinetically modelled. Thermal processing caused a gradual decrease in sugars, which was accompanied by the formation of brown pigments and 5-hydroxymethylfurfural, increased concentration of soluble solids as evaluated through refractive index measurements, as well as the appearance of darker colors. In particular, a zero-order kinetic model could explain the changes in H° and reducing sugars, while the evolution of refractive index, brown pigments, 5-hydroxymethylfurfural, C*, fructose, and glucose were best fitted using a first-order kinetics model.     

Chemical Composition and Evaluation of Insecticidal Activity of Calendula incana subsp. maritima and Laserpitium siler subsp. siculum Essential Oils against Stored Products Pests

The problems of the environment and human health related to the use of synthetic and broad-spectrum insecticides have increasingly motivated scientific research on different alternatives and among these, the use of green systems, such as essential oils, have been explored. Several species of the Apiaceae and Asteraceae families, aromatic herbs rich in secondary bioactive metabolites, are used in the industrial field for pharmaceutical, cosmetic, and food purposes. Different essential oils extracted from some species of these families have shown acute toxicity and attractive and/or repellent effects towards different insects. In our work, we investigated the toxic potential of Calendula incana subsp. maritima and Laserpitium siler subsp. siculum essential oils against four insect species, Sitophilus oryzae, Lasioderma serricorne, Necrobia rufipes, and Rhyzoperta dominica, which are common pests of stored products. The composition of both oils, extracted by hydrodistillation from the aerial parts of the two plants, was evaluated by GC×GC-MS. Calendula incana subsp. maritima essential oil was rich in oxygenated sesquiterpenoids, such as cubebol (35.39%), 4-epi-cubebol (22.99%), and cubenol (12.77%), while the Laserpitium siler subsp. siculum essential oil was composed mainly of monoterpene hydrocarbons, such as β-phellandrene (42.16%), limonene (23.87%), and β-terpinene (11.80%). The toxicity Petri dish bioassays indicated that C. maritima oil killed a mean of 65.50% of S. oryzae and 44.00% of R. dominica adults, indicating a higher biocidal activity in comparison with L. siculum oil, while toward the other species, no significant differences in mortality were recorded. Calendula maritima oil could be, then, considered a promising candidate for further tests as an alternative biocide toward S. oryzae and R. dominica. The possibility that the relatively high content of oxygenated sesquiterpenoids in C. maritima essential oil determines its higher biocidal activity is discussed.     

Phenolic Compound Profile by UPLC-MS/MS and Encapsulation with Chitosan of Spondias mombin L. Fruit Peel Extract from Cerrado Hotspot—Brazil

Taperebá (Spondias mombin L.) is a native species of the Brazilian Cerrado that has shown important characteristics such as a significant phenolic compound content and biological activities. The present study aimed to characterize the phenolic compound profile and antioxidant activity in taperebá peel extract, as well as microencapsulating the extract with chitosan and evaluating the stability of the microparticles. The evaluation of the profile of phenolic compounds was carried out by UPLC-MS/MS. The in vitro antioxidant activity was evaluated by DPPH and ABTS methods. The microparticles were obtained by spray drying and were submitted to a stability study under different temperatures. In general, the results showed a significant content of polyphenols and antioxidant activity. The results of UPLC-MS/MS demonstrated a significant content of polyphenols in taperebá peel, highlighting the high content of ellagic acid and quercetin compounds. There was significant retention of phenolic compounds when microencapsulated, demonstrating high retention at all evaluated temperatures. This study is the first to microencapsulate the extract of taperebá peel, in addition to identifying and quantifying some compounds in this fruit.     

Components of Banisteriopsis caapi,a Plant Used in the Preparation of the Psychoactive Ayahuasca,Induce Anti-Inflammatory Effects in Microglial Cells

Banisteriopsis caapi is used to prepare the psychoactive beverage ayahuasca, and both have therapeutic potential for the treatment of many central nervous system (CNS) conditions. This study aimed to isolate new bioactive compounds from B. caapi extract and evaluate their biological activity, and that of the known β-carboline components of the plant (harmine, harmaline, and tetrahydroharmine), in BV-2 microglial cells, the in vivo activation of which is implicated in the physiopathology of CNS disorders. B. caapi extract was fractionated using semipreparative liquid chromatography (HPLC-DAD) and the exact masses ([M + H]⁺ m/z) of the compounds in the 5 isolated fractions were determined by high-resolution LC-MS/MS: F1 (174.0918 and 233.1289), F2 (353.1722), F3 (304.3001), F4 (188.1081), and F5 (205.0785). Harmine (75.5–302 µM) significantly decreased cell viability after 2 h of treatment and increased the number of necrotic cells and production of reactive oxygen species at equal or lower concentrations after 24 h. F4 did not impact viability but was also cytotoxic after 24 h. Most treatments reduced proinflammatory cytokine production (IL-2, IL-6, IL-17, and/or TNF), especially harmaline and F5 at 2.5 µM and higher concentrations, tetrahydroharmine (9.3 µM and higher), and F5 (10.7 µM and higher). The results suggest that the compounds found in B. caapi extract have anti-inflammatory potential that could be explored for the development of treatments for neurodegenerative diseases.     

The Bifurcated σ-Hole···σ-Hole Stacking Interactions

The bifurcated σ-hole···σ-hole stacking interactions between organosulfur molecules, which are key components of organic optical and electronic materials, were investigated by using a combined method of the Cambridge Structural Database search and quantum chemical calculation. Due to the geometric constraints, the binding energy of one bifurcated σ-hole···σ-hole stacking interaction is in general smaller than the sum of the binding energies of two free monofurcated σ-hole···σ-hole stacking interactions. The bifurcated σ-hole···σ-hole stacking interactions are still of the dispersion-dominated noncovalent interactions. However, in contrast to the linear monofurcated σ-hole···σ-hole stacking interaction, the contribution of the electrostatic energy to the total attractive interaction energy increases significantly and the dispersion component of the total attractive interaction energy decreases significantly for the bifurcated σ-hole···σ-hole stacking interaction. Another important finding of this study is that the low-cost spin-component scaled zeroth-order symmetry-adapted perturbation theory performs perfectly in the study of the bifurcated σ-hole···σ-hole stacking interactions. This work will provide valuable information for the design and synthesis of novel organic optical and electronic materials.     

Quality Related Safety Evaluation of a South African Traditional Formulation (PHELA®) as Novel Anti-Biofilm Candidate

A South African traditional formulation, PHELA^®, is consumed by the traditional people for severe chest problems with coughing, diarrhea, oral ulcers etc. The present study focused on establishing the anti-infective properties of a safe and standardized poly-herbal formulation through a series of criteria and specifications.     

Accumulation of Particles and Formation of a Dissipative Structure in a Nonequilibrium Bath

The standard textbooks contain good explanations of how and why equilibrium thermodynamics emerges in a reservoir with particles that are subjected to Gaussian noise. However, in systems that convert or transport energy, the noise is often not Gaussian. Instead, displacements exhibit an α-stable distribution. Such noise is commonly called Lévy noise. With such noise, we see a thermodynamics that deviates from what traditional equilibrium theory stipulates. In addition, with particles that can propel themselves, so-called active particles, we find that the rules of equilibrium thermodynamics no longer apply. No general nonequilibrium thermodynamic theory is available and understanding is often ad hoc. We study a system with overdamped particles that are subjected to Lévy noise. We pick a system with a geometry that leads to concise formulae to describe the accumulation of particles in a cavity. The nonhomogeneous distribution of particles can be seen as a dissipative structure, i.e., a lower-entropy steady state that allows for throughput of energy and concurrent production of entropy. After the mechanism that maintains nonequilibrium is switched off, the relaxation back to homogeneity represents an increase in entropy and a decrease of free energy. For our setup we can analytically connect the nonequilibrium noise and active particle behavior to entropy decrease and energy buildup with simple and intuitive formulae.