Identification of Novel Rab27a/Melanophilin Blockers by Pharmacophore-Based Virtual Screening

Melanocytes are unique cells that produce specific melanin-containing intracellular organelles called melanosomes. Melanosomes are transported from the perinuclear area of melanocytes toward the plasma membrane as they become more melanized in order to increase skin pigmentation. In this vesicular trafficking of melanosomes, Rab27a, melanophilin, and myosin Va play crucial roles in linking melanosomes to actin-based motors. To identify novel compounds to inhibit binding interface between Rab27a and melanophilin, a pharmacophore model was built based on a modeled 3D structure of the protein complex that describes the essential binding residues in the intermolecular interaction. A pharmacophore model was employed to screen a chemical library database. Finally, 25 virtual hits were selected for biological evaluations. The biological activities of 11 analogues were evaluated in a second assay. Two compounds were identified as having concentration-dependent inhibitory activity. By analyzing structure–activity relationships of derivatives of BMD-20, two hydroxyl functional groups were found to be critical for blocking the intermolecular binding between Rab27a and melanophilin.     

Oversampling Free Energy Perturbation Simulation in Determination of the Ligand-Binding Free Energy

Determination of the ligand-binding affinity is an extremely interesting problem. Normally, the free energy perturbation (FEP) method provides an appropriate result. However, it is of great interest to improve the accuracy and precision of this method. In this context, temperature replica exchange molecular dynamics implementation of the FEP computational approach, which we call replica exchange free energy perturbation (REP) was proposed. In particular, during REP simulations, the system can easily escape from being trapped in local minima by exchanging configurations with high temperatures, resulting in significant improvement in the accuracy and precision of protein–ligand binding affinity calculations. The distribution of the decoupling free energy was enlarged, and its mean values were decreased. This results in changes in the magnitude of the calculated binding free energies as well as in alteration in the binding mechanism. Moreover, the REP correlation coefficient with respect to experiment ( R^REP = 0.85 ± 0.15 ) is significantly boosted in comparison with the FEP one ( R^FEP = 0.64 ± 0.30 ). Furthermore, the root-mean-square error (RMSE) of REP is also smaller than FEP, RMSE^REP = 4.28 ± 0.69 versus RMSE^FEP = 5.80 ± 1.11 kcal/mol, respectively. © 2019 Wiley Periodicals, Inc.     

An Activatable AIEgen Probe for High‐Fidelity Monitoring of Overexpressed Tumor Enzyme Activity and Its Application to Surgical Tumor Excision

Monitoring fluctuations in enzyme overexpression facilitates early tumor detection and excision. An AIEgen probe (DQM‐ALP) for the imaging of alkaline phosphatase (ALP) activity was synthesized. The probe consists of a quinoline‐malononitrile (QM) core decorated with hydrophilic phosphate groups as ALP‐recognition units. The rapid liberation of DQM‐OH aggregates in the presence of ALP resulted in aggregation‐induced fluorescence. The up‐regulation of ALP expression in tumor cells was imaged using DQM‐ALP. The probe permeated into 3D cervical and liver tumor spheroids for imaging spatially heterogeneous ALP activity with high spatial resolution on a two‐photon microscopy platform, providing the fluorescence‐guided recognition of sub‐millimeter tumorigenesis. DQM‐ALP enabled differentiation between tumor and normal tissue ex vivo and in vivo, suggesting that the probe may serve as a powerful tool to assist surgeons during tumor resection.     

γ‐Glutamylcysteine‐ and Cysteinylglycine‐Directed Growth of Chiral Gold Nanoparticles and their Crystallographic Analysis

Chiral optical metamaterials with delicate structures are in high demand in various fields because of their strong light–matter interactions. Recently, a scalable strategy for the synthesis of chiral plasmonic nanoparticles (NPs) using amino acids and peptides has been reported. Reported herein, 3D chiral gold NPs were synthesized using dipeptide γ‐Glu‐Cys and Cys‐Gly and analyzed crystallographically. The γ‐Glu‐Cys‐directed NPs present a cube‐like outline with a protruding chiral wing. In comparison, the NPs synthesized with Cys‐Gly exhibited a rhombic dodecahedron‐like outline with curved edges and elliptical cavities on each face. Morphology analysis of intermediates indicated that γ‐Glu‐Cys generated an intermediate concave hexoctahedron morphology, while Cys‐Gly formed a concave rhombic dodecahedron. NPs synthesized with Cys‐Gly are named 432 helicoid V because of their unique morphology and growth pathway.     

Triterpene glycosides from the Vietnamese sea cucumber Holothuria edulis

Abstract

From the MeOH extract of the Vietnamese sea cucumber Holothuria edulis, eight triterpene glycosides (1–8), including one new compound namely holothurin A₅ (1), were isolated by using various chromatographic separations. Their structures were established by spectroscopic experiments including 1D, 2D NMR and HR-ESI-MS. Holothurin A₅ (1) has a hydroperoxy group at C-25. To the best of our knowledge, this is the first report of this group in triterpene saponins obtained from sea cucumbers to date. In addition, the in vitro cytotoxicity against five human cancer cell lines (HepG2, KB, LNCaP, MCF7 and SK-Mel2) of all isolated compounds was also evaluated using SRB assays.     

Simultaneous separation and determination of 20 potential adulterant antigout and antiosteoporosis pharmaceutical compounds in herbal food products using LC with electrospray ionization MS/MS and LC with quadrupole‐time‐of‐flight MS

An analytical method for the simultaneous and reliable determination of 20 antigout and antiosteoporosis pharmaceutical compounds in adulterated health food products was developed using liquid chromatography with electrospray ionization tandem mass spectrometry and liquid chromatography with quadrupole‐time‐of‐flight mass spectrometry. The method was validated through the determination of specificity, linearity, limit of detection, and limit of quantification, method detection limit, method quantitation limit, precision, accuracy, recovery, and stability. The matrix effect was also determined. The validation results of the developed method are as follows: for solid and liquid blank samples, limits of detection ranged from 0.05 to 5.00 ng/mL and limits of quantification ranged from 0.15 to 15.00 ng/mL. Linearity was acceptable, and the correlation coefficients (R²) were ≥0.99 for all target compounds. Both intra and interday precision were less than 9.16% RSD, and accuracies ranged from 95.31 to 116.68%. Mean recoveries for different types of dietary supplements classified as powders, liquids, tablets, and capsules were found to be 80.81 to 117.62% with less than 15.00% relative standard deviation. The stability of the standard mixture solution was less than 11.72% relative standard deviation after 48 h. By the proposed method, the presence of dexamethasone was determined in seized herbal food products at concentrations that ranged from 126 to 215 µg/g.     

Optical modes in nanoscale one-dimensional spin chains

The spin chain systems with one-dimensional magnetic ordering are promising candidates for quantum optical devices. This paper shows how the optical excitation can induce various phonon modes in an ideal Cu-O chain at various lengths. The calculation was carried out at different level theories including configuration interaction singles for excited states, density functional theory and second-order Möller-Plesset perturbation. In general, the number of modes increases with chain length due to growing asymmetry of atomic positions when chain exceeds 5 nm. There were, however, only two basic modes: one is associated with the symmetric oscillation of oxygen and another with the asymmetric motion of the same along the chain. At the length below 4.3 nm, the Raman activity of the symmetric mode (440 cm⁻¹) dominates. From analysis of density of states, this mode may be associated with the excitation across the lowest LUMO bands with changing in spin state.     

Dalitz analysis of D0-->K(0)(S)pi(+)pi(-)

In e(+)e(-) collisions using the CLEO detector, we have studied the decay of the D0 to the final state K(0)(S)pi(+)pi(-) with the initial flavor of the D0 tagged by the decay D(*+)-->D0pi(+). We use the Dalitz technique to measure the resonant substructure in this final state and clearly observe ten different contributions by fitting for their amplitudes and relative phases. We observe a K(*)(892)(+)pi(-) component which arises from doubly Cabibbo suppressed decays or D0-D0; mixing.     

Observation of B-->K(0)(S)pi(+)pi(-) and Evidence for B-->K(*+/-)pi(-/+)

We report on a search for charmless hadronic B decays to the three-body final states K(0)(S)h(+)pi(-), K(+)h(-)pi(0), K(0)(S)h(+)pi(0) (h(+/-) denotes a charged pion or kaon), and their charge conjugates, using 13.5 fb(-1) of integrated luminosity produced near sqrt[s]=10.6 GeV, and collected with the CLEO detector. We observe the decay B-->K0pi(+)pi(-) with a branching fraction (50(+10)(-9)(stat.)+/-7(syst.))x10(-6) and the decay B-->K(*+)(892)pi(-) with a branching fraction (16(+6)(-5)(stat.)+/-2(syst.))x10(-6).