Stacking Gaussian processes to improve $$pK_a$$ p K a predictions in the SAMPL7 challenge

Journal of Computer-Aided Molecular Design - Accurate predictions of acid dissociation constants are essential to rational molecular design in the pharmaceutical industry and elsewhere. There has...     

Teaching the Chemistry of Platinum

Following colonisation of South America by the Spanish, many new naturally occurring substances were sent to Europe. One of these was the silvery, unreactive metal, platinum, discovered in New Grenada in the mid-eighteenth century. It was often found in granular form, associated with gold, and the challenge to chemists was to refine it, produce it as wire or sheet, and determine its chemical properties. This interested the professor of chemistry at the University of Edinburgh, Joseph Black, who was able to obtain samples from London-based Spanish contacts, particularly Ignacio Luzuriaga. This paper examines how Black transmitted his knowledge of the metal to large numbers of students attending his annual course.     

Selective Catalytic Isomerization of β-Pinene Oxide to Perillyl Alcohol Enhanced by Protic Tetraimidazolium Nitrate

A series of tetraimidazolium salts with different anions was prepared and applied in the isomerization of β-pinene oxide. After examining the activity of different catalysts, a remarkable enhancement of the selectivity of perillyl alcohol (47 %) was obtained over [PEimi][HNO₃]₄ under mild reaction conditions and using DMSO as the solvent. Furthermore, noncovalent interactions between solvent molecules and the catalyst were found by FT-IR spectroscopy and confirmed by computational chemistry. The homogeneous catalyst showed excellent stability and was reused up to six times without significant loss.     

Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.     

Physical aging in amorphous poly(ethylene furanoate): Enthalpic recovery,density, and oxygen transport considerations

The current work utilizes three separate techniques to study the physical aging process in amorphous poly(ethylene furanoate) (PEF), which is a recently introduced engineering thermoplastic with enhanced properties compared to petroleum‐sourced poly(ethylene terephthalate). Differential scanning calorimetry aging experiments were conducted at multiple aging temperatures and times, and the resultant enthalpic recovery values compared to the theoretical maximum enthalpy loss evaluated from calculations involving extrapolation of the equilibrium liquid line. Density measurements reveal densification of the matrix for the aged versus unaged samples, and provide an estimate for the reduction in free volume for the aged samples. Complementary oxygen permeation and pressure‐decay sorption experiments provide independent verification of the free volume reduction mechanism for physical aging in glassy polymers. The current work provides the first detailed aging study for PEF. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 389–399