Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets

We have designed four generations of a low molecular weight fragment library for use in NMR-based screening against protein targets. The library initially contained 723 fragments which were selected manually from the Available Chemicals Directory. A series of in silico filters and property calculations were developed to automate the selection process, allowing a larger database of 1.79 M available compounds to be searched for a further 357 compounds that were added to the library. A kinase binding pharmacophore was then derived to select 174 kinase-focused fragments. Finally, an additional 61 fragments were selected to increase the number of different pharmacophores represented within the library. All of the fragments added to the library passed quality checks to ensure they were suitable for the screening protocol, with appropriate solubility, purity, chemical stability, and unambiguous NMR spectrum. The successive generations of libraries have been characterized through analysis of structural properties (molecular weight, lipophilicity, polar surface area, number of rotatable bonds, and hydrogen-bonding potential) and by analyzing their pharmacophoric complexity. These calculations have been used to compare the fragment libraries with a drug-like reference set of compounds and a set of molecules that bind to protein active sites. In addition, an analysis of the overall results of screening the library against the ATP binding site of two protein targets (HSP90 and CDK2) reveals different patterns of fragment binding, demonstrating that the approach can find selective compounds that discriminate between related binding sites.     

Continuous sample deposition from reversed-phase liquid chromatography to tracks on a matrix-assisted laser desorption/ionization precoated target for the analysis of protein digests

Peptide mass fingerprinting by matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry (MS) is one of the standard high-throughput methods for protein identification today. Traditionally this method has been based on spotting peptide mixtures onto MALDI targets. While this method works well for more abundant proteins, low-abundance proteins mixed with high-abundance proteins tend to go undetected due to ion suppression effects, instrumental dynamic range limitations and chemical noise interference. We present an alternative approach where liquid chromatography (LC) effluent is continuously collected as linear tracks on a MALDI target. In this manner the chromatographic separation is spatially preserved on the target, which enables generation of off-line LC-MS and LC-MS/MS data by MALDI. LC-MALDI sample collection provides improved sensitivity and dynamic range, spatial resolution of peptides along the sample track, and permits peptide mass mapping of low-abundance proteins in mixtures containing high-abundance proteins. In this work, standard and ribosomal protein digests are resolved and captured using LC-MALDI sample collection and analyzed by MALDI-TOF-MS.     

Experimental and Computational Study of the Thermal Decomposition of 3‐Methyl‐3‐buten‐1‐ol in m‐Xylene Solution

An experimental study of the thermal decomposition of a β‐hydroxy alkene, 3‐methyl‐3‐buten‐1‐ol, in m‐xylene solution, has been carried out at five different temperatures in the range of 513.15–563.15 K. The temperature dependence of the rate constants for the decomposition of this compound in the corresponding Arrhenius equation is given by ln k (s^?1) = (25.65 ± 1.52) ? (17,944 ± 814) (kJ·mol^?1)·T^?1. A computational study has been carried out at the M05–2X/6–31+G(d,p) level of theory to calculate the rate constants and the activation parameters by the classical transition state theory. There is a good agreement between the experimental and calculated rate constants and activation Gibbs energies. The bonding characteristics of reactant, transition state, and products have been investigated by the natural bond orbital analysis, which provides the natural atomic charges and the Wiberg bond indices. Based on the results obtained, the mechanism proposed is a one‐step process proceeding through a six‐membered cyclic transition state, being a concerted and slightly asynchronous process. The results have been compared with those obtained previously by us (Struct Chem 2013, 24, 1811–1816) for the thermal decomposition of 3‐buten‐1‐ol, in m‐xylene solution. We can conclude that in the compound studied in this work, 3‐methyl‐3‐buten‐1‐ol, the effect of substitution at position 3 by a weakly activating CH₃ group is the stabilization of the transition state formed in the reaction and therefore a small increase in the rate of thermal decomposition.     

Structural and Kinetic Aspects of Blood Plasma Protein Adsorption on the Surface of Hydrophobic Polymers

Abstract

Due to the wide use of polymers in medicine, researchers are required to solve a very important problem–to understand the interaction between materials of nonphysiological origin and the surrounding biological liquids, and tissues, particularly blood.     

Thermochemistry of fluorine compounds: IV. Rubidium tetrafluoroiodate

From measurement of the heat of hydrolysis, at 25°C , the enthalpy of formation of rubidium tetrafluoroiodate is derived: ΔH°_f [RbIF₄, cryst.]₂₉₈= ?191.12±4.43 kJ mol^?1. Heat capacity measurements for RbIF₄ over the range 273–303 K are also reported.     

Mai?analytische Bestimmung von Schwefels?ure, Salpeters?ure und salpetriger S?ure in Misch- und Abfalls?uren

Ohne Zusammenfassung