Quantum mechanics approaches to drug research in the era of structural chemogenomics

The rapid growth of the available crystallographic information about proteins and binding pockets creates remarkable opportunities for enriching the drug research pipelines with computational prediction of novel protein–ligand interactions. While ab initio quantum mechanical (QM) approaches are known to provide unprecedented accuracy in structure‐based binding energy calculations, they are limited to only small systems of dozens of atoms. In the structural chemogenomics era, it is critical that new approaches are developed that enable application of QM methodologies to noncovalent interactions in systems as large as protein–ligand complexes and conformational ensembles. This perspective highlights recent advances towards bridging the gap between high‐accuracy and high‐volume computations in drug research. © 2013 Wiley Periodicals, Inc.     

Novel Procedure for the Coupling of Sterically Hindered Electron-Deficient Anilines to the 6-Position of the Purine Core

Sterically hindered electron-deficient anilines are coupled to the 6-position of the purine core only when activated as their corresponding TFA-amide. The free anilines did not react under all conditions tested. After aqueous work-up, the TFA-group is lost.

This procedure provides a new tool in the construction of purines functionalized with a sterically hindered electron-deficient aniline in the 6-position.      

Determination of polycyclic aromatic hydrocarbon metabolites in milk by a quick,easy, cheap,effective, rugged and safe extraction and capillary electrophoresis

We describe the first application of a quick, easy, cheap, effective, rugged and safe extraction technique to the CZE analysis of monohydroxylated metabolites of polycyclic aromatic hydrocarbons in milk. Complete resolution of 2‐hydroxyfluorenene, 1‐hydroxynaphthalene, 2‐hydroxynaphthalene, 3‐hydroxyphenanthrene, and 9‐hydroxyphenanthrene was accomplished in 4 min of electrophoretic run. Limits of detection at the parts‐per‐billion were obtained with a single solvent (acetonitrile) for metabolite extraction and sample stacking. The small sample volume (1.2 mL) and the conservative usage of chemicals provided a simple and rapid procedure for the simultaneous extraction of numerous samples. Adding 4 min of electrophoretic run per sample, it should be possible to screen ten samples in approximately 1 h of analysis time. The nanoliter extract volume required for sample injection allows for further chromatographic usage and confirmation of positive samples. The unique electrophoretic pattern of the studied metabolites demonstrates the potential for the unambiguous determination of positional isomers with very similar chromatographic behaviors and undistinguishable mass fragmentation patterns.     

Experimental investigation of the effect of initial fuel particle shape, size and bed temperature on devolatilization of single wood particle in a hot fluidized bed

Considerable amount of investigation on the subject of devolatilization of wood is found in the open literature. However, a systematic study of the effect of initial particle size and shape, and bed temperature on devolatilization time and char yield of wood in a hot fluidized bed is still missing. This paper attempts to fill this gap through a systematic experimental investigation to determine the devolatilization time and char yield of a typical woody biomass, “Casuarina equisetifolia” particles of different initial sizes and shapes at various fluidized bed temperatures. Experiments are conducted using 10, 15, 20, and 25 mm Casuarina wood particles of three shapes, namely, cube, cylinder, and sphere at bed temperatures of 1023, 1123, and 1223 K.It is found that the initial wood particle size has the strongest influence on devolatilization time followed by the shape of initial wood particle and the bed temperature. Correlation for devolatilization time (τ_d) as a function of initial wood particle size (d_eq), sphericity (?), and bed temperature (T_b), is developed using 573 experimental data points exhibiting a correlation coefficient of 0.96 and predictions falling well within a deviation band of ±20%. The predictions of the present correlation are compared with the predictions of the existing correlations in literature for conditions also out of the present study and the deviation is found to be ±30%.Char yield, defined as the ratio of the residual mass at the end of devolatilization process to the initial mass of the wood particle is found to be in the range of 9-14% for all sizes, shapes, and bed temperatures. Char yield does not depict any definite trend with the variation of initial particle size, shape and bed temperature.     

Analysis of co-eluted isomers of high-molecular weight polycyclic aromatic hydrocarbons in high performance liquid chromatography fractions via solid-phase nanoextraction and time-resolved Shpol'skii spectroscopy

We present an accurate method for the determination of isomers of high-molecular weight polycyclic aromatic hydrocarbons co-eluted in HPLC fractions. The feasibility of this approach is demonstrated with two isomers of molecular weight 302 with identical mass fragmentation patterns, namely dibenzo[a,i]pyrene and naphtho[2,3-a]pyrene. Qualitative and quantitative analysis is carried out via laser-excited time-resolved Shpol'skii spectroscopy at liquid helium temperature. Unambiguous identification of co-eluted isomers is based on their characteristic 4.2 K line-narrowed spectra in n-octane as well as their fluorescence lifetimes. Pre-concentration of HPLC fractions prior to spectroscopic analysis is performed with the aid of gold nanoparticles via an environmentally friendly procedure. In addition to the two co-eluted isomers, the analytical figures of merit of the entire procedure were evaluated with dibenzo[a,l]pyrene, dibenzo[a,h]pyrene and dibenzo[a,e]pyrene. The analytical recoveries from drinking water samples varied between 98.2±5.5 (dibenzo[a,l]pyrene) and 102.7±3.2% (dibenzo[a,i]pyrene). The limits of detection ranged from 51.1 ng L(-1) (naphtho[2,3-a]pyrene) to 154 ng L(-1) (dibenzo[a,e]pyrene). The excellent analytical figures of merit associated to its HPLC compatibility makes this approach an attractive alternative for the analysis of co-eluted isomers with identical mass spectra.     

Performance of hexamer peptide ligands for affinity purification of immunoglobulin G from commercial cell culture media

Previous work has reported on the identification and characterization of the hexapeptide ligands HWRGWV, HYFKFD, and HFRRHL for the affinity capture of IgG through specific binding to its Fc fragment. This paper addresses issues related to the successful application of these ligands, on a commercial methacrylate chromatographic resin, for the purification of IgG from mammalian cell culture fluids. The concentrations of sodium chloride and sodium caprylate in the binding buffer were optimized to maximize the purity and yield of IgG upon elution. Screening of several regeneration conditions found that either 2M guanidine-HCl or a combination of 0.85% phosphoric acid followed by 2M urea resulted in complete recovery of the IgG adsorption capacity and that the column could be reused over many cycles. The hexapeptide ligands were used for the purification of humanized and chimeric monoclonal antibodies from two commercial CHO cell culture fluids. The chimeric MAb of IgG1 subclass was purified using the HWRGWV resin whereas the humanized MAb of IgG4 subclass was purified using the HWRGWV, HYFKFD and HFRRHL resins. The purities and yields obtained for both the MAbs were found to be higher than 94% and 85% respectively. These results compare well with the yields and purities obtained using Protein G columns. The residual DNA and host cell protein reduction obtained by the HWRGWV resin was in the range of 4 log reduction value (LRV) and 2 LRV respectively, comparable to those reported for Protein A resins. The dynamic binding capacity of all three peptide resins for the humanized monoclonal antibody was in the range of 20mg/mL.     

On influence of collimating slit imperfections on the quality of experimental data in high-resolution x-ray diffraction

High-resolution x-ray diffraction and imaging techniques commonly assume a well-defined plane wave incident on the sample. Experimentally, the wave-front is limited by a collimating slit. Slit imperfections, such as surface roughness on the edges, may significantly contribute to the formation of the diffraction pattern from a specimen placed behind the slit. These effects become more profound when imaging at the nano-scale. This Letter presents experimental and simulated x-ray diffraction data quantitatively demonstrating the influence of slit edge imperfections on the formation of the diffraction pattern in the far-field regime.     

Turbulent statistical characteristics associated to the north wind phenomenon in southern Brazil with application to turbulent diffusion

A parameterization for the transport processes in a shear driven planetary boundary layer (PBL) has been established employing turbulent statistical quantities measured during the north wind phenomenon in southern Brazil. Therefore, observed one-dimensional turbulent energy spectra are compared with a spectral model based on the Kolmogorov arguments. The good agreement obtained from this comparison leads to well defined formulations for the turbulent velocity variance, local decorrelation time scale and eddy diffusivity. Furthermore, for vertical regions in which the wind shear forcing is relevant, the eddy diffusivity derived from the north wind data presents a similar profile to those obtained from the non-extensive statistical mechanics theory. Finally, a validation for the present parameterization has been accomplished, using a Lagrangian stochastic dispersion model. The Prairie Grass data set, which presents high mean wind speed, is simulated. The analysis developed in this study shows that the turbulence parameterization constructed from wind data for north wind flow cases is able to describe the diffusion in a high wind speed, shear-dominated PBL.     

Effective action in a general chiral model: Next to leading order derivative expansion in the worldline method

We present a formalism to determine the imaginary part of a general chiral model in the derivative expansion. Our formalism is based on the worldline path integral for the covariant current that can be given in an explicit chiral and gauge covariant form. The effective action is then obtained by integrating the covariant current, taking account of the anomaly.