GC-MS,LC-MS/MS,Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2′-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3β-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of −87.91, −78.11, and −68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.     

Reactivity of phosphiranes toward nucleophiles: Theoretical and experimental investigations

The thermodynamic and kinetic parameters for the reaction of 1‐methylphosphirane with dimethylphosphide (PMe), proceeding via attack at the ring phosphorus atom to give Me₂P–PMe⁻ plus ethylene, were calculated at the G3(MP2)‐RAD(+) level. The rate constant for this mechanism (k = 1.1 × 10¹³ L mol⁻¹ s⁻¹ at 25°C) is seven orders of magnitude greater than that for the previously studied mechanism involving attack at carbon. Experimental investigations with 1‐phenylphosphirane gave consistent results: Treatment with LiPMePh yielded no detectable polymer, and quenching with MeI gave the known diphosphine (R*, R*)‐(±)/(R*, S*)‐MePhP‐‐PMePh. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:178–181, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20405     

Molecular Docking and Molecular Dynamics Studies of Antidiabetic Phenolic Compound Isolated from Leaf Extract of Englerophytum magalismontanum (Sond.) T.D.Penn.

Englerophytum magalismontanum, a medicinal plant with ethnopharmacology use, has a dearth of information regarding its antidiabetic properties. This study evaluated the crude methanol leaf extract of E. magalismontanum and its fractions for total phenolic content, antioxidant activity, and digestive enzymes (α-amylase and α-glucosidase) inhibitory activity using standard methods. The total phenolic content (56.53 ± 1.94 mg GAE/g dry extract) and DPPH Trolox antioxidant equivalent (TAE) (1.51 ± 0.66 µg/mL) of the methanol fraction were the highest among the fractions. The IC₅₀ values of the methanol fraction against α-amylase (10.76 ± 1.33 µg/mL) and α-glucosidase (12.25 ± 1.05 µg/mL) activities were also high. Being the most active, the methanol fraction was subjected to bio-assay guided column chromatography-based enzyme inhibition to obtain a pure compound. The phenolic compound isolated and identified as naringenin inhibited α-amylase and α-glucosidase with IC₅₀ of 5.81 ± 2.14 µg/mL and 4.77 ± 2.99 µg/mL, respectively. This is the first study to isolate naringenin from E. magalismontanum extract. The molecular docking and molecular dynamics studies demonstrated naringenin as a promising lead compound in comparison to acarbose for the treatment of diabetes through the inhibition of α-glucosidase activity.     

Multivariate Analysis Revealed Ultrasonic-Assisted Extraction Improves Anti-Melanoma Activity of Non-Flavonoid Compounds in Indonesian Brown Algae Ethanol Extract

Indonesia has high biodiversity of algae that are under-utilised due to limitations in the processing techniques. Here, we observed the effect of two different extraction methods (cold maceration and ultrasonic-assisted extraction (UAE)) on multiple variables of Indonesian brown algae ethanol extracts (Sargassum polycystum, Sargassum cristaefolium, Sargassum aquifolium and Turbinaria ornata). The variables observed included metabolites screening by untargeted metabolomics liquid chromatography-high-resolution mass spectrometry (LC-HRMS), observation of total phenolic content (TPC), total flavonoid content (TFC), anti-oxidant and B16-F10 melanoma cells cytotoxicity. UAE extracts had higher extraction yield and TPC, but no TFC difference was observed. UAE extract had more lipophilic compounds, such as fatty acids (Palmitic acid, Oleamide, Palmitoleic acid, Eicosapentaenoic acid, α-Linolenic acid, Arachidonic acid), lipid-derived mediators (11,12-Epoxyeicosatrienoic acid ((±)11(12)-EET)), steroid derivatives (Ergosterol peroxide), lipophilic metabolite (Fucoxanthin), and lipid-soluble vitamins (all-trans-retinol). Principle component analysis (PCA) revealed that TPC, not TFC, in the UAE extracts was correlated with the anti-oxidant activities and cytotoxicity of the extracts towards B16-F10 melanoma cells. This means other non-flavonoid phenolic and lipophilic compounds may have contributed to its bioactivity. These results suggest that out of the two methods investigated, UAE could be a chosen method to extract natural anti-melanogenic agents from brown algae.     

Development water in oil nanoemulsion of diethylcarbamazine for enhanced the characteristics for lymphatic targeting: A proof of concept study

As an antifilariasis drug, oral administration of diethylcarbamazine (DEC) could not effectively deliver the drug to the lymphatic system. Hydrophobic formulation with a particle size of <100 nm could improve the delivery of drug. Accordingly, we developed water in oil nanoemulsion encapsulating DEC. The nanoemulsion was less than 100 nm with negative charge, showing its suitability for lymphatic targeting. The nanoemulsion could sustain the release of DEC and improve the retention in intestinal tissue in comparison with DEC solution. Importantly, this approach did not cause any hemolysis in in vitro study and any irritation in in vivo study.     

Computational Study of Asian Propolis Compounds as Potential Anti-Type 2 Diabetes Mellitus Agents by Using Inverse Virtual Screening with the DIA-DB Web Server,Tanimoto Similarity Analysis,and Molecular Dynamic Simulation

Propolis contains a wide range of pharmacological activities because of their various bioactive compounds. The beneficial effect of propolis is interesting for treating type-2 diabetes mellitus (T2DM) owing to dysregulation of multiple metabolic processes. In this study, 275 of 658 Asian propolis compounds were evaluated as potential anti-T2DM agents using the DIA-DB web server towards 18 known anti-diabetes protein targets. More than 20% of all compounds could bind to more than five diabetes targets with high binding affinity (<−9.0 kcal/mol). Filtering with physicochemical and pharmacokinetic properties, including ADMET parameters, 12 compounds were identified as potential anti-T2DM with favorable ADMET properties. Six of those compounds, (2R)-7,4′-dihydroxy-5-methoxy-8-methylflavone; (RR)-(+)-3′-senecioylkhellactone; 2′,4′,6′-trihydroxy chalcone; alpinetin; pinobanksin-3-O-butyrate; and pinocembrin-5-methyl ether were first reported as anti-T2DM agents. We identified the significant T2DM targets of Asian propolis, namely retinol-binding protein-4 (RBP4) and aldose reductase (AKR1B1) that have important roles in insulin sensitivity and diabetes complication, respectively. Molecular dynamic simulations showed stable interaction of selected propolis compounds in the active site of RBP4 and AKR1B1. These findings suggest that Asian propolis compound may be effective for treatment of T2DM by targeting RBP4 and AKR1B1.     

Applications of Crank-Nicolson method with ADI in laser transformation hardening

A two-dimensional numerical solution for pulsed laser transformation hardening is developed using the finite difference method (FDM). The FDM has been developed using Crank-Nicolson scheme which solved by using alternating-direction implicit method. If this present model was compared to the analytical solution, then the Crank-Nicolson scheme showed better results in terms of accuracy, consistency, stability, convergence, and performance than to the explicit scheme. The longer heating duration, higher laser beam intensity, and greater number of pulse had influences on increasing the maximum temperature. The repetitive heating had influences on extending the heat duration and increasing the initial temperature of domain. The shorter cooling duration in repetitive pulse produced higher maximum temperature. The thinner material’s thickness increased the cooling rate, which finally increased the possibility of austenite to transform into martensite phase. In addition, it was also found that the higher maximum temperature always reduced the cooling rate value when temperature cools down toward to the starting temperature of martensite formation. It reduced the possibility of martensite formation. It was also seen that the heat was conducted more effective to the axial direction than to the radial direction.     

The Chemical Scaffold of Theranostic Radiopharmaceuticals: Radionuclide,Bifunctional Chelator,and Pharmacokinetics Modifying Linker

Therapeutic radiopharmaceuticals have been researched extensively in the last decade as a result of the growing research interest in personalized medicine to improve diagnostic accuracy and intensify intensive therapy while limiting side effects. Radiometal-based drugs are of substantial interest because of their greater versatility for clinical translation compared to non-metal radionuclides. This paper comprehensively discusses various components commonly used as chemical scaffolds to build radiopharmaceutical agents, i.e., radionuclides, pharmacokinetic-modifying linkers, and chelators, whose characteristics are explained and can be used as a guide for the researcher.