Molecular Environment Research Articles

Molecular Docking Assessment of Limonoids from Cameroonian Entandrophragma Species as Potential Inhibitors of Anopheles gambiae Acetylcholinesterase (AChE)

Malaria remains one of the great killers in tropical regions of the world due to the transmission of the Plasmodium parasite by the bites of the female mosquito Anopheles. The resistance of this species to synthetic insecticides contributes to an increase in the incidence of malaria and therefore necessitates the development of new potent and eco-friendly insecticides. In this study, twelve previously reported limonoids from four Entandrophragma species collected in Cameroon have been computationally evaluated for their Anopheles gambiae AChE inhibitory activity. The docking procedure was carried out through Molecular Operating Environment 2019.01 (MOE), while the UCSF Chimera program was used to model the docking results based on interactions between proteins and ligands, and molecular dynamics trajectories were analyzed using the GROMACS 2021.1 tool. Entandrophragmin and encandollens B and C with docking scores ranging from −6.45 to −7.28 kcal/mol were the most promising hits compared to the reference azadirachtin (−6.22 kcal/mol) and were further evaluated for their mechanism of action. Subsequent evaluation classified encandollen C as the best candidate for the development of new potent eco-friendly insecticides based on its lower average RMSD and RMSF and its compactness over a 150 ns duration with acetylcholinesterase.

Phase-Sensitive Fluorescence Image Correlation Spectroscopy.

Fluorescence lifetime imaging microscopy is sensitive to molecular interactions and environments. In homo-dyne frequency-domain fluorescence lifetime imaging microscopy, images of fluorescence objects are acquired at different phase settings of the detector. The detected intensity as a function of detector phase is a sinusoidal function that is sensitive to the lifetime of the fluorescent species. In this paper, the theory of phase-sensitive fluorescence image correlation spectroscopy is described. In this version of lifetime imaging, image correlation spectroscopy analysis (i.e., spatial autocorrelation) is applied to successive fluorescence images acquired at different phase settings of the detector. Simulations of different types of lifetime distributions reveal that the phase-dependent density of fluorescent objects is dependent on the heterogeneity of lifetimes present in the objects. We provide an example of this analysis workflow to a cervical cancer cell stained with a fluorescent membrane probe.

Electroinduced Reductive and Dearomative Alkene-Aldehyde Coupling.

The direct coupling of alkene feedstocks with aldehydes represents an expedient approach to the generation of new and structurally diverse C(sp3)-hybridized alcohols that are primed for elaboration into privileged architectures. Despite their abundance, current disconnection strategies enabling the direct coupling of carbon-carbon π-bonds and aldehydes remain challenging because contemporary methods are often limited by substrate or functional group tolerance and compatibility in complex molecular environments. Here, we report a coupling between simple alkenes, heteroarenes and unactivated aliphatic aldehydes via an electrochemically induced reductive activation of C-C π-bonds. The cornerstone of this approach is the discovery of rapid alternating polarity (rAP) electrolysis to access and direct highly reactive radical anion intermediates derived from conjugated alkenes and heterocyclic compounds. Our developed catalyst-free protocol enables direct access to new and structurally diverse C(sp3)-hybridized alcohol products. This is achieved by the controlled reduction of conjugated alkenes and the C2-C3 π-bond in heteroarenes via an unprecedented reductive dearomative functionalization for heterocyclic compounds. Experimental mechanistic studies demonstrate a kinetically biased single-electron reduction of C-C π-bonds over aldehydes. Application of rAP enables chemoselective generation of olefinic radical anion intermediates and avoids undesired saturative overreduction. Overall, this technology provides a versatile approach to the reductive coupling of olefin and heterocycle feedstocks with aliphatic aldehydes, offering straightforward access to diverse C(sp3)-rich oxygenated scaffolds.

Ultrafast T1-T1ρ NMR for Correlating Different Motional Regimes of Molecules.

Nuclear magnetic resonance (NMR) relaxation times provide detailed information about molecular motions and local chemical environments. Longitudinal T1 relaxation time is most often sensitive to relatively fast, nano- to picosecond ranges of molecular motion. Rotating frame T1ρ relaxation time reflects a much slower, micro- to millisecond range of motion, and the motional regime can be tuned by changing spin-lock field strength. Conventional methods for measuring T1 and T1ρ relaxation times are time-consuming, since experiments must be repeated many times with incremented magnetization recovery or decay delay. In this work, we introduce two novel and efficient NMR methods to correlate the T1 and T1ρ relaxation times. The first method, IR-SPICY, combines the conventional T1 inversion recovery (IR) with the single-scan T1ρ detection-based spin-lock cycle (SPICY). The second method, ultrafast (UF) IR-SPICY, allows measurement of whole two-dimensional T1-T1ρ correlation data in a single scan, in a couple of seconds, based on spatial encoding of the T1 dimension. We demonstrate the performance of the methods by studying relaxation of water in porous silica and hydrogel samples, latter acting as a model of the articular cartilage extracellular matrix. The methods allow correlating different molecular motional regimes, potentially providing unprecedented information about various chemical and biochemical systems, such as structures and fluid dynamics in porous materials, macromolecular changes in tissues, and protein dynamics. One to three orders of magnitude shortened experiment time enable the studies of changing or degrading samples. Furthermore, the single-scan approach may significantly facilitate the use of modern nuclear-spin hyperpolarization techniques to enhance the sensitivity of T1-T1ρ measurements by several orders of magnitude.

Switchable protection and exposure of a sensitive squaraine dye within a redox active rotaxane

In nature, molecular environments in proteins can sterically protect and stabilize reactive species such as organic radicals through non-covalent interactions. Here, we report a near-infrared fluorescent rotaxane in which the stabilization of a chemically labile squaraine fluorophore by the coordination of a tetralactam macrocycle can be controlled chemically and electrochemically. The rotaxane can be switched between two co-conformations in which the wheel either stabilizes or exposes the fluorophore. Coordination by the wheel affects the squaraine’s stability across four redox states and renders the radical anion significantly more stable—by a factor of 6.7—than without protection by a mechanically bonded wheel. Furthermore, the fluorescence properties can be tuned by the redox reactions in a stepwise manner. Mechanically interlocked molecules provide an excellent scaffold to stabilize and selectively expose reactive species in a co-conformational switching process controlled by external stimuli.

Studi Molecular Docking dan Evaluasi Farmakokinetik Senyawa Analog Pirazol Turunan Benzen-Sulfonilurea sebagai Inhibitor Enzim Aldose Reduktase and α-Glukosidase Menggunakan Pendekatan In Silico

The pyrazole scaffold modification in various chemical structures on several studies has shown various biopharmacological activities. This study aims to predict the potential inhibition of pyrazole analogs derived benzene-sulfonylurea (4A, 4B, 4E, 5A, 5C, 5D) against the α-glucosidase (3A4A) and aldose reductase (3RX2) enzymes based on a molecular docking approach using Molecular Operating Environment (MOE) 2020.0102 software and evaluate pharmacokinetic profile (ADMET). In this study, the six test compounds were obtained from previous studies that have been proven antihyperglycemic. The results showed that all the 3,5-disubstituted benzene-sulfonylurea derivative pyrazole analogs are predicted to have low inhibitory activity against the α-glucosidase enzyme. Further, all compounds showed good aldose reductase inhibitor activity and had lower binding free energy values ​​than tolrestat as the positive control (-6.82 kcal/mol). Compound 5C has the best potential inhibitory activity against the aldose reductase enzyme compared to the other test compounds, because it has the lowest binding free energy value (-8.76 kcal/mol) and interacts with important residues on the receptor forming four hydrogen bonds, namely the carbonyl group of SO2 with residues Trp111 and His110, and the carbonyl group of the amide with residues His110 and Tyr48, as well as 3 hydrophobic bonds, namely a pyrazole ring with residues Leu300, Trp219 and a furan ring with Phe122. ADMET properties of the compounds are also predicted. This information provides an opportunity for a 5C compound as an aldose reductase inhibitor agent to develop drug candidates with better and safer activities.

In-silico Molecular Docking of Two Bioactive Constituents (Quercetin 3-Glucuronide and Quercitrin) from Polygonum minus Leaves into Monoamine Oxidase-A Crystal Structure

The aim of the current research was to dock the two abundant bioactive constituents of Polygonum minus leaf extract, in1cluding Quercetin 3-Glucuronide (Miquelianin) and Quercitrin (Quercetin-3-rhamnoside). In-silico Molecular modelling technique was used to predict about a protein (enzyme) interacts with molecules (ligands). Monoamine oxidase-A (MAO-A) is the key enzyme that is involved in the breakdown of neurotransmitters like serotonin and noradrenaline. Drugs that are involved in its inhibition, are considered to be antidepressant agents. This molecular docking study observed the binding energy of selected ligands and their interactions with amino acid residue along with bond types in the MAO-A structure. Molecular docking was done using Molecular Operating Environment (MOE) software, whereas visualization and expression of results were carried out using Discovery Studio (DS) visualizer. Clorgyline was used in this study as a co-crystal ligand, whereas moclobemide was used as a standard MAO-A inhibitor, and Amitriptyline was used as a common antidepressant which also has some MAO-A inhibitory effect. Quercetin 3-glucuronide (Miquelianin) and Quercitrin (Quercetin-3-rhamnoside) have more binding affinities with MAO-A structure as compared to all other drugs. Its interaction pattern was most likely moclobemide and Clorgyline, which are considered standard MAO-A inhibitors in this study. Based on these results, it is concluded that Quercetin 3-Glucuronide (Miquelianin) and Quercitrin (Quercetin-3-rhamnoside) have the potential to become potent MAO-A inhibitors in future.

Insights into the enhanced adsorption of glyphosate by dissolved organic matter in farmland Mollisol: effects and mechanisms of action.

Dissolved organic matter (DOM) is easy to combine with residual pesticides and affect their morphology and environmental behavior. Given that the binding mechanism between DOM and the typical herbicide glyphosate in soil is not yet clear, this study used adsorption experiments, multispectral techniques, density functional theory, and pot experiments to reveal the interaction mechanism between DOM and glyphosate on Mollisol in farmland and their impact on the environment. The results show that the adsorption of glyphosate by Mollisol is a multilayer heterogeneous chemical adsorption process. After adding DOM, due to the early formation of DOM and glyphosate complex, the adsorption process gradually became dominated by single-layer chemical adsorption, and the adsorption capacity increased by 1.06 times. Glyphosate can quench the endogenous fluorescence of humic substances through a static quenching process dominated by hydrogen bonds and van der Waals forces, and instead enhance the fluorescence intensity of protein substances by affecting the molecular environment of protein molecules. The binding of glyphosate to protein is earlier, of which affinity stronger than that of humic acid. In this process, two main functional groups (C-O in aromatic groups and C-O in alcohols, ethers and esters) exist at the binding sites of glyphosate and DOM. Moreover, the complexation of DOM and glyphosate can effectively alleviate the negative impact of glyphosate on the soil. This study has certain theoretical guidance significance for understanding the environmental behavior of glyphosate and improving the sustainable utilization of Mollisol.

A Novel Technique for Fluorescence Lifetime Tomography.

Fluorescence lifetime has emerged as a unique imaging modality for quantitatively assessing in vivo the molecular environment of diseased tissues. Although fluorescence lifetime microscopy (in 2D) is a mature field, 3D imaging in deep tissues remains elusive and challenging owing to scattering. Herein, we report on a deep neural network (coined AUTO-FLI) that performs both 3D intensity and quantitative lifetime reconstructions in deep tissues. The proposed Deep Learning (DL)-based approach involves an in silico scheme to generate fluorescence lifetime data accurately. The developed DL model is validated both in silico and on experimental phantoms. Overall, AUTO-FLI provides accurate 3D quantitative estimates of both intensity and lifetime distributions in highly scattering media, demonstrating its unique potential for fluorescence lifetime-based molecular imaging at the mesoscopic and macroscopic scale.

Disulfide Bond Engineering of Soluble ACE2 for Thermal Stability Enhancement.

Although the primary pandemic of SARS-CoV-2 is over, there are concerns about the resurgence of the next wave of related viruses, including a wide range of variant viruses. The soluble ACE2 (sACE2) inhibits the SARS-CoV-2 spike protein ACE2 interaction and has potential as a variant-independent therapeutic against SARS-CoV-2. Here, we introduce novel disulfide bonds in the wild-type sACE2-Fc by structure-guided mutagenesis, aiming to improve its stability. The stability of each mutant was assessed by a thermal shift assay to screen mutants with increased thermal stability. As a result, we identified a mutant sACE2-Fc with a significantly increased melting temperature. X-ray crystal structure determination of the sACE2 mutant confirmed the correct formation of the designed disulfide bond, and there were no significant structural disturbances. We also proved that the thermostable sACE2-Fc preserved the spike protein binding affinity comparable to the wild-type sACE2-Fc in both molecular and cellular environments, suggesting its therapeutic potential.

Prediction of Listeria monocytogenes Clonal Complexes from Multilocus Variable Number Tandem Repeat Analysis Patterns Using a Machine Learning Approach.

Multilocus variable number tandem repeat analysis (MLVA) is a molecular subtyping technique that remains useful for those without the resources to access whole genome sequencing for the tracking and tracing of bacterial contaminants. Unlike techniques such as multilocus sequence typing (MLST) and pulsed-field gel electrophoresis, MLVA did not emerge as a standardized subtyping method for Listeria monocytogenes, and as a result, there is no reference database of virulent or food-associated MLVA subtypes as there is for MLST-based clonal complexes (CCs). Having previously shown the close congruence of a 5-loci MLVA scheme with MLST, a predictive model was created using the XGBoost machine learning (ML) technique, which enabled the prediction of CCs from MLVA patterns with ∼85% (±4%) accuracy. As well as validating the model on existing data, a straightforward update protocol was simulated for if and when previously unseen subtypes might arise. This article illustrates how ML techniques can be applied with elementary coding skills to add value to previous-generation molecular subtyping data in-built food processing environments.

Absorption line broadening in atomic beams produced in a molecular beam epitaxy environment

Absorption line broadening in atomic beams produced in a molecular beam epitaxy environment

Magnetohydrodynamical modeling of star-disk formation: from isolated spherical collapse towards incorporation of external dynamics

The formation of protostars and their disks has been understood as the result of the gravitational collapse phase of an accumulation of dense gas that determines the mass reservoir of the star-disk system. Against this background, the broadly applied scenario of considering the formation of disks has been to model the collapse of a dense core assuming spherical symmetry. Our understanding of the formation of star-disk systems is currently undergoing a reformation though. The picture evolves from interpreting disks as the sole outcome of the collapse of an isolated prestellar core to a more dynamic picture where disks are affected by the molecular cloud environment in which they form. In this review, we provide a status report of the state-of-the-art of spherical collapse models that are highly advanced in terms of the incorporated physics together with constraints from models that account for the possibility of infall onto star-disk systems in simplified test setups, as well as in multi-scale simulations that cover a dynamical range from the Giant Molecular Cloud environment down to the disk. Considering the observational constraints that favor a more dynamical picture of star formation, we finally discuss the challenges and prospects in linking the efforts of tackle the problem of star-disk formation in combined multi-scale, multi-physics simulations.

Asian Spice Nanotech: Illicium verum made Metal Nanoparticles for Potent Antibacterial and Catalytic Applications

Introduction: Asian spices are globally recognized for their rich phytochemical composition. The bioactive compounds of Asian spices have significant potential to extend the biological applications of metal nanomaterials by increasing their surface area, stability, dispersion, and ecofriendliness. Method: The present study is designed to prepare novel iron oxide (Fe2O3) and copper oxide (CuO) nanoparticles using an aqueous extract of Illicium verum (star anise), a traditional Asian spice as a reducing, capping & stabilizing agent. The synthesized nanoparticles have been characterized to study their molecular environment using Fourier-transform infrared spectroscopy (FTIR). Elemental composition was examined through the Energy dispersive X-ray Spectroscopy (EDS). Scanning Electron Microscopy (SEM) revealed the size, shape, and other morphological characteristics of nanoparticles. The optical properties have been tested through Ultraviolet-Visible (UV) spectroscopy and the band gap energies of both Fe2O3 and CuO nanoparticles have been calculated by using the Tauc plot method, which explores its semiconductor applications. The catalytic applications of obtained nanoparticles have shown significant potential in the degradation of aqueous methyl orange dye (MO). Results: Results revealed that Fe2O3 and CuO nanoparticles significantly increased the rate of reaction by decreasing the reaction time to 45 mins and 40 mins, respectively in comparison to the NaBH4 (60 mins). This shows that CuO has a larger surface area and more absorption capacity than Fe2O3 NPs. To examine the cause of value healthcare, the obtained materials have also been applied against various Gram-positive and Gram-negative bacteria. The bactericidal activity was compared with gentamicin, which showed both nanometals are moderate to strongly active against tested microbes. Conclusion: The successful eco-friendly synthesis of metallic nanoparticles by using Asian spices and their applications in physical and biological sciences opens the door for the scientific community to develop and apply more novel and green nanomaterials in industrial and commercial areas.

Similarity Metrics for Subcellular Analysis of FRET Microscopy Videos.

Understanding the heterogeneity of molecular environments within cells is an outstanding challenge of great fundamental and technological interest. Cells are organized into specialized compartments, each with distinct functions. These compartments exhibit dynamic heterogeneity under high-resolution microscopy, which reflects fluctuations in molecular populations, concentrations, and spatial distributions. To enhance our comprehension of the spatial relationships among molecules within cells, it is crucial to analyze images of high-resolution microscopy by clustering individual pixels according to their visible spatial properties and their temporal evolution. Here, we evaluate the effectiveness of similarity metrics based on their ability to facilitate fast and accurate data analysis in time and space. We discuss the capability of these metrics to differentiate subcellular localization, kinetics, and structures of protein-RNA interactions in Forster resonance energy transfer (FRET) microscopy videos, illustrated by a practical example from recent literature. Our results suggest that using the correlation similarity metric to cluster pixels of high-resolution microscopy data should improve the analysis of high-dimensional microscopy data in a wide range of applications.

Single-molecule diffusivity quantification in Xenopus egg extracts elucidates physicochemical properties of the cytoplasm.

The complex intracellular molecular environment is notably challenging to elucidate and recapitulate. Xenopus egg extracts provide a native yet manipulatable cytoplasm model. Through single-molecule microscopy, here we decipher the cytoplasmic environment and molecular interactions by examining the diffusion patterns of diverse proteins in Xenopus egg extracts with strategic manipulations. These experiments reveal an overwhelmingly negatively charged macromolecular environment with crosslinked meshworks, offering new insight into the inner workings of the cell.

Infrared Spectra of Solid HCN Embedded in Various Molecular Environments for Comparison with the Data Obtained with JWST

Hydrogen cyanide (HCN) molecules serve as an important tracer for the chemical evolution of elemental nitrogen in the regions of star and planet formation. This is largely explained by the fact that N atoms and N2 molecules are poorly accessible for observation in the radio and infrared (IR) ranges. In turn, gas-phase HCN can be observed at various stages of star formation, including disks around young stars, cometary comas, and atmospheres of the planetary satellites. Despite the large geography of gas-phase observations, an identification of interstellar HCN ice is still lacking. In this work we present a series of IR spectroscopic measurements performed at the new ultrahigh vacuum cryogenic apparatus aiming to facilitate the search for interstellar HCN ice. A series of high-resolution laboratory IR spectra of HCN molecules embedded in the H2O, H2O:NH3, CO, CO2, and CH3OH ices at 10 K temperature is obtained. These interstellar ice analogues aim to simulate the surroundings of HCN molecules by the main constituents of the icy mantles on the surface of the interstellar grains. In addition, the spectra of HCN molecules embedded in the solid C6H6, C5H5N, and C6H5NH2 are obtained to somehow simulate the interaction of HCN molecules with carbonaceous material of the grains rich in polycyclic aromatic hydrocarbons. The acquired laboratory spectroscopic data are compared with the publicly available results of NIRSpec James Webb Space Telescope observations toward quiescent molecular clouds performed by the IceAge team.

One pot multi-component synthesis of novel functionalized pyrazolo furan-2(5H)-one derivatives: in vitro, DFT, molecular docking, and pharmacophore studies, as coronavirus inhibitors.

New and facile one-pot approach for the syntheses of 12 derivatives of 3,5-disubstituted furane-2(5H)-one (4a-l) from easily available starting materials. The suitable synthetic procedures for selective synthesis of diverse furane-2(5H)-one derivatives were achieved via multi-component condensation of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde (1), pyruvic acid and different aromatic amines 3a-l in good to high yields and short reaction time by refluxing in acetic acid as well as obtained by another method (method B) when unsaturated arylidene pyruvic acid 6 was refluxed with different aromatic amines in acetic acid but in smaller yield than method A. Structures of the prepared compounds were elucidated by elemental analysis and spectral data as mass, IR, 1H-NMR and 13C-NMR spectroscopy. The antiviral efficacy of compounds 4a-l against SARS-CoV-2 was evaluated using the MTT assay. It was demonstrated that synthetic compounds 4c-e and 4h-j have a potent and selective inhibitory effect on SARS-CoV-2, a strain obtained from Egyptian patients. We utilized density-functional theory (DFT) analyses to deduce the molecular structures and topologies of the more energetic molecules. Molecular docking studies were performed against the SARS-CoV-2 main protease (PDB ID: 6Y84) and the SARS-CoV-2 Nsp9 RNA binding protein (PDB ID: 6W4B) to study the binding mechanism, non-bonding interactions, and binding affinity. Lastly, a hypothetical pharmacophore model was constructed by applying the Molecular Operating Environment (MOE) tool and eleven pharmaceuticals with proven antiviral activity.

Parabolic-like Trend in SiO Ratios throughout the Central Molecular Zone: Possible Signature of a Past Nuclear Activity in the Galactic Center

We report the discovery of a characteristic trend in the intensity ratios of SiO emissions across the Central Molecular Zone (CMZ) of our Galaxy. Using the Nobeyama Radio Observatory 45 m telescope, we conducted large-scale, high-sensitivity imaging observations in molecular lines including SiO J = 2–1 and CS J = 2–1. By identifying SiO-emitting clouds and examining their intensity ratios relative to the other molecular lines, we unveiled a parabolic-like trend showing lower ratios near the Galactic nucleus, Sgr A*, with gradual increases toward the edges of the CMZ. This pattern suggests a possible outburst of the nucleus within the last ∼105 yr, which may have propagated through the entire CMZ with strong shocks. Alternatively, the observed trend may also be attributed to the destruction of small dust grains by high-energy photons. Our results can potentially lead to a new perspective on the history of nuclear activity and its impact on the surrounding molecular environment.

Multifaceted regulation of chiroptical properties and self‐assembly behaviors of chiral fluorescent polymers

AbstractThe multifaceted regulation of the chiroptical properties and self‐assembly behaviors of chiral fluorescent polymers is of great significance yet remains challenging to achieve. Herein, a series of novel salen‐based chiral fluorescent polymers with aggregation‐induced emission and varied substitution manners were facilely and efficiently synthesized. Multiple factors were systematically investigated on the chiroptical properties and self‐assembly performance of these polymers, which include molecular structures, solvent environments, metal coordination, and liquid crystal (LC) assemblies. Sutle change in the solvent composition can lead to diverse assembly morphologies of all these chiral polymers, from single‐handed helical fibers, helical toroids or loops, to spherical structures, consequently leading to an aggregation‐reduced circular dichroism (CD) phenomenon. The polymers bearing salen units show highly selective and reversible coordination with Zn2+ and can also induce multiple responses in the absorption, luminescence, CD, and circularly polarized luminescence (CPL) of these chiral fluorescent polymers via a coordination‐ and dissociation‐initiated self‐assembly tuning. Furthermore, a small amount of the chiral fluorescent polymer in can induce achiral nematic 4‐cyano‐4′‐n‐pentylbiphenyl (5CB) to form ordered chiral nematic LC phase with significant improvement in their CD and CPL signal. The absolute absorption and luminescent dissymmetry factors of the resulting supramolecular assemblies can reach the order of 10−1.