Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

The HYDE scoring function consistently describes hydrogen bonding, the hydrophobic effect and desolvation. It relies on HYdration and DEsolvation terms which are calibrated using octanol/water partition coefficients of small molecules. We do not use affinity data for calibration, therefore HYDE is generally applicable to all protein targets. HYDE reflects the Gibbs free energy of binding while only considering the essential interactions of protein-ligand complexes. The greatest benefit of HYDE is that it yields a very intuitive atom-based score, which can be mapped onto the ligand and protein atoms. This allows the direct visualization of the score and consequently facilitates analysis of protein-ligand complexes during the lead optimization process. In this study, we validated our new scoring function by applying it in large-scale docking experiments. We could successfully predict the correct binding mode in 93% of complexes in redocking calculations on the Astex diverse set, while our performance in virtual screening experiments using the DUD dataset showed significant enrichment values with a mean AUC of 0.77 across all protein targets with little or no structural defects. As part of these studies, we also carried out a very detailed analysis of the data that revealed interesting pitfalls, which we highlight here and which should be addressed in future benchmark datasets.     

Clean-up method for determination of established and emerging brominated flame retardants in dust

A clean-up method was developed to enable the determination of tri-decabrominated diphenyl ethers, isomer-specific hexabromocyclododecanes (HBCDs), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), decabromodiphenyl ethane (DBDPE), (2-ethylhexyl)tetrabromobenzoate (TBB), and bis(2-ethylhexyl)tetrabromophthalate (TBPH) in the same dust sample extract using reasonable amounts of solvents and without dividing the sample. After extraction, the sample was separated on a silica column into three fractions that were subsequently cleaned up individually. The polybrominated diphenyl ethers (PBDEs) and DBDPE were eluted in Fraction I, TBB, TBPH, and BTBPE in Fraction II, and HBCDs in Fraction III. Fractions I and II were analyzed using gas chromatography/mass spectrometry and Fraction III using liquid chromatography/mass spectrometry. The method gave good recoveries (60-120%), precise results using (13)?C-labelled internal standards and was accurate when comparing results to certified values (PBDEs in NIST SRM 2585). The method was applied to dust samples from the Stockholm (Sweden) area. All the emerging brominated flame retardants (BFRs) studied, except BTBPE, were present in all the samples in quantifiable concentrations, often higher than the PBDEs. BTBPE was quantified in only one sample. It is evident that emerging BFRs are present in Swedish homes, and these compounds should be included in the BFR analyses of indoor environments.     

Determination of 1-hydroxypyrene in human urine by HPLC with electrochemical detection at a boron-doped diamond film electrode

A high-performance liquid chromatographic method with electrochemical detection (HPLC-ED) at a boron-doped diamond film electrode with preliminary separation and preconcentration by solid-phase extraction (SPE) has been developed for the determination of 1-hydroxypyrene (1-HP) in human urine. 1-HP is among the most widely used biomarkers of exposure to polycyclic aromatic hydrocarbons. Optimal HPLC-ED conditions have been found: mobile phase methanol-0.05 mol L(-1) phosphate buffer pH 5.0 (80:20, v/v), detection potential +1,000 mV versus Ag/AgCl (3 mol L(-1) KCl), and flow rate 0.8 mL min(-1). For SPE, LiChrolut(?) RP-18 E cartridges were used. The extraction yield was (87.0 ± 5.8)% (n = 5). The concentration dependence of 1-HP was measured in the concentration range from 0.01 to 10 μmol L(-1) (2.18-2,180 μg L(-1)) using methanolic solutions resulting from the SPE pretreatment of spiked human urine samples. The limit of detection (signal-to-noise ratio 3) and the limit of quantification (signal-to-noise ratio 10) of the biomarker were 0.013 μmol L(-1) (2.84 μg L(-1)) and 0.043 μmol L(-1) (9.39 μg L(-1)), respectively, which is sufficient for its determination in the urine of persons exposed to polycyclic aromatic hydrocarbons.     

A New Approach to High Sensitivity Liquid Chromatography-Mass Spectrometry of Peptides using Nanoflow Solvent Assisted Inlet Ionization

Liquid chromatography (LC) solvent assisted inlet ionization (SAII) mass spectrometry (MS) was previously reported to give good chromatographic resolution and MS detection injecting 66 ng of a BSA tryptic digest. In analogy to nano-electrospray ionization (nESI), we extend SAII LC/MS to nano-SAII (nSAII) operating at nL min^–1 flow rates and demonstrate good quality ion chromatograms and mass spectra from injection of as little as 0.7 ng of BSA digest onto a capillary LC column. Data dependent fragmentation is demonstrated for injection of 7 ng of a BSA digest. This method has advantages over nESI in ease of use and low cost as it requires no voltage and is operational without the necessity of connectors or fragile nESI emitters, although similar constricted tips can be helpful in nSAII to stabilize the signal at low nanoliter flow. At a flow rate of 0.8 μL min^–1, the only requirement for nSAII is that the exit-end of the capillary LC column be adjusted near the aperture of the heated inlet of the mass spectrometer.     

Intermolecular interactions in nitrogen-containing aromatic systems

π–π and CH···N interactions are vital in biological systems. In this study, stacking and hydrogen-bonded interactions in pyrazine and triazine dimers were investigated by density functional theory combined with symmetry-adapted perturbation theory (DFT-SAPT) and counterpoise (CP)-corrected supermolecular MP2, SCS-MP2, B3LYP-D and CCSD(T) calculations. All interaction energies were computed using the optimized structures at the CP-corrected SCS/aug-cc-pVDZ level, which gave 1–2 kJ/mol lower interaction energies than the ones computed at the MP2 level. For both dimers, doubly hydrogen-bonded and cross-(displaced) stacked orientations were found to be the lowest energy ones. The reference CCSD(T) calculations favored the former structure in both dimer systems, whereas MP2 and SCS-MP2 located the latter as the lowest energy isomer. In particular, the former was found to be lower in energy than the latter by 2.28 and 1.01 kJ/mol at the CCSD(T)/aug-cc-pVDZ level for pyrazine and triazine, respectively. B3LYP-D produced interaction energies in agreement with the CCSD(T) at the equilibrium geometries, but it overestimates them at the short range and underestimates at the long intermonomer separations. Furthermore, it tends to give smaller equilibrium distances compared to the CCSD(T). DFT-SAPT method was in a good agreement with the reference CCSD(T) calculations. This suggests that DFT-SAPT can be employed to compute the full potential energy surface of these dimers. Moreover, DFT-SAPT calculations showed that the electrostatic and dispersion contributions are the most important energy components stabilizing these dimers. The present study aims to show which theoretical method is the most promising one for the investigation of intermolecular interactions dominated by π–π and CH···N. Therefore, the findings obtained in this study can be used to unravel the structures of nucleic acid bases and other systems stabilized by π–π and CH···N interactions.     

On the protonated state of amidinium-like diaromatic derivatives: X-ray and UV studies

We present the crystal structures of the chloride salts of the mono-guanidinium 1 (–CH₂CH₂– linker) and the bis-isouronium 2 (–O– linker) that have been resolved by us indicating that these compounds are diprotonated in the solid state as informed by the counterions positions. To determine the pK _a values of these compounds as well as those of their analogues 3 (mono-2-aminoimidazolinium with a –CH₂CH₂– linker) and 4 (mono-guanidinium with a –O– linker), the corresponding UV–Vis titrations were carried out. Thus, in aqueous solution compounds 1, 3 and 4 were present as mono-cationic species while derivative 2 was a bis-cation.     

Online monitoring of coffee roasting by proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS): towards a real-time process control for a consistent roast profile

A real-time automated process control tool for coffee roasting is presented to consistently and accurately achieve a targeted roast degree. It is based on the online monitoring of volatile organic compounds (VOC) in the off-gas of a drum roaster by proton transfer reaction time-of-flight mass spectrometry at a high time (1 Hz) and mass resolution (5,500 m/Δm at full width at half-maximum) and high sensitivity (better than parts per billion by volume). Forty-two roasting experiments were performed with the drum roaster being operated either on a low, medium or high hot-air inlet temperature (= energy input) and the coffee (Arabica from Antigua, Guatemala) being roasted to low, medium or dark roast degrees. A principal component analysis (PCA) discriminated, for each one of the three hot-air inlet temperatures, the roast degree with a resolution of better than ±1 Colorette. The 3D space of the three first principal components was defined based on 23 mass spectral profiles of VOCs and their roast degree at the end point of roasting. This provided a very detailed picture of the evolution of the roasting process and allowed establishment of a predictive model that projects the online-monitored VOC profile of the roaster off-gas in real time onto the PCA space defined by the calibration process and, ultimately, to control the coffee roasting process so as to achieve a target roast degree and a consistent roasting.     

The effect of loading and particle size on the oxygen reaction in CGO impregnated Pt electrodes

Porous platinum electrodes impregnated with Gd _x Ce_1−x O_2−δ (CGO) are investigated to characterise how nano-sized CGO grains affect the oxygen reaction. Impedance measurements were performed at temperatures between 450 and 750 °C and at oxygen partial pressures of 0.2 and 5 × 10⁻⁵ bar for electrodes with various CGO loadings and electrodes annealed at various temperatures. The morphology was characterised by scanning electron microscopy and the CGO grain size was determined from X-ray diffraction peak broadening. The results showed that the polarisation resistance decreased with increasing CGO loading and increasing annealing temperature. CGO facilitates transport of oxygen ions thereby increasing the effective triple-phase boundary.     

Syntheses and modifications of bisdiazonium salts of 3,8-benzo[c]cinnoline and 3,8-benzo[c]cinnoline 5-oxide onto glassy carbon electrode and the characterization of the modified surfaces

The goal of this study was to prepare novel glassy carbon electrode surfaces using two similar bis-diazonium salts, 3,8-benzo[c]cinnoline (3,8-BCC-BDAS) and 3,8-benzo[c]cinnoline 5-oxide (3,8-BCCNO-BDAS) at the glassy carbon (GC) surface. These diazonium salts were reduced electrochemically and covalently electrografted onto the glassy carbon electrode surface to form modified electrodes. Electrochemical reduction of 3,8-BCC-BDAS and 3,8-BCCNO-BDAS salts on the electrode surface yielded a compact and stable film. The existence of BCC moieties on the GC surface was characterized by X-ray photoelectron spectroscopy, reflectance-adsorption infrared spectroscopy, cyclic voltammetry, ellipsometry, and electrochemical impedance spectroscopy. The stability and working potential range of the novel modified electrodes were also studied. The possibility of analytical application of these novel surfaces for inorganic cations and especially selectivity to copper ions was investigated. 3,8-diaminobenzo[c]cinnoline (3,8-DABCC) and its 5-oxide derivative (3,8-DABCCNO) were synthesized from the reductive cyclization of 2,2′-dinitrobenzidine and prepared their bisdiazonium salts via the tetrazotization reactions of the diamines with NaNO₂. The structures of 3,8-DABCC and 3,8-DABCCNO and their corresponding bisdiazonium salts are confirmed by spectral analysis.