Electron spin lifetimes in Hg0.78Cd0.22 Te and InSb

We have made direct pump–probe measurements of spin lifetimes in long wavelength narrow-gap semiconductors at wavelengths between 4 and 10 μm and from 4 to 300 K. In particular, we measure remarkably long spin lifetimes, τ_s300 ps, even at 300 K for epilayers of degenerate n-type InSb. In this material the mobility is approximately constant between 77 and 300 K, and we find that τ_s is approximately constant in this temperature range. In order to determine the dominant spin relaxation mechanism we have investigated the temperature dependence of τ_s in non-degenerate lightly n-type Hg_0.78Cd_0.22Te of approximately the same band gap as InSb, and find that τ_s varies from 356 ps at 150 K to 24 ps at 300 K. Our results, both in magnitude and temperature dependence of τ_s, imply that the Elliott–Yafet model dominates in these materials.     

PROPERTIES OF THE ULTRAVIOLET-LIGHT-MEDIATED BINDING OF BOVINE SERUM ALBUMIN TO DNA*

Abstract— The binding of DNA to protein mediated by U V (254 nm) radiation has been investigated using binding of the complex to Millipore membrane filters as an assay technique. The reaction proceeds through an activated protein intermediate which then reacts with the DNA. The activated protein has a half-life of about 75 min at 0°C and about 18 min at 37°C. Short wavelengths are more efficient in forming the complex than wavelengths in the 250–280 nm range. N-ethyl maleimide treatment of protein before irradiation markedly inhibits the reaction.     

Bigger data,collaborative tools and the future of predictive drug discovery

Over the past decade we have seen a growth in the provision of chemistry data and cheminformatics tools as either free websites or software as a service commercial offerings. These have transformed how we find molecule-related data and use such tools in our research. There have also been efforts to improve collaboration between researchers either openly or through secure transactions using commercial tools. A major challenge in the future will be how such databases and software approaches handle larger amounts of data as it accumulates from high throughput screening and enables the user to draw insights, enable predictions and move projects forward. We now discuss how information from some drug discovery datasets can be made more accessible and how privacy of data should not overwhelm the desire to share it at an appropriate time with collaborators. We also discuss additional software tools that could be made available and provide our thoughts on the future of predictive drug discovery in this age of big data. We use some examples from our own research on neglected diseases, collaborations, mobile apps and algorithm development to illustrate these ideas.     

Novel Synthesis of (+/−)-cis-4-Amino-2-cyclopentene-1-methanol,a Key Intermediate in the Preparation of Carbocyclic 2′,3′-Didehydro-2′,3′-dideoxy Nucleosides

Abstract

Novel synthetic routes directed toward the preparation of (+/?)-cis -4-amino-2-cyclopentene-1-methanol are described. The routes investigated involve azide openings of chiral and non-chiral cyclopentyl epoxides.     

Towards a new age of virtual ADME/TOX and multidimensional drug discovery

With the continual pressure to ensure follow-up molecules to billion dollar blockbuster drugs, there is a hurdle in profitability and growth for pharmaceutical companies in the next decades. With each success and failure we increasingly appreciate that a key to the success of synthesized molecules through the research and development process is the possession of drug-like properties. These properties include an adequate bioactivity as well as adequate solubility, an ability to cross critical membranes (intestinal and sometimes blood-brain barrier), reasonable metabolic stability and of course safety in humans. Dependent on the therapeutic area being investigated it might also be desirable to avoid certain enzymes or transporters to circumvent potential drug-drug interactions. It may also be important to limit the induction of these same proteins that can result in further toxicities. We have clearly moved the assessment of in vitro absorption, distribution, metabolism, excretion and toxicity (ADME/TOX) parameters much earlier in the discovery organization than a decade ago with the inclusion of higher throughput systems. We are also now faced with huge amounts of ADME/TOX data for each molecule that need interpretation and also provide a valuable resource for generating predictive computational models for future drug discovery. The present review aims to show what tools exist today for visualizing and modeling ADME/TOX data, what tools need to be developed, and how both the present and future tools are valuable for virtual filtering using ADME/TOX and bioactivity properties in parallel as a viable addition to present practices.     

Chemical reactivity and surface-enhanced raman scattering

A mechanism is proposed for surface-enhanced Raman scattering for pyridine which explains the enhancement, the anodizalion “activation”, the significance of silver, the photographitization of coordinated pyridine and formate, the participation of surface roughness, and the irreversibly held yet liquid-like nature of surface pyridine.     

Synthesis of 3-vinylpiperidine

A novel synthesis of 3-vinylpiperidine from commercially available ethyl 3-pyridylacetate is described.     

Comparison of 14C-amino acid mixture and [35S]methionine labeling of cellular proteins from mouse fibroblast C3H10T1/2 cells by two-dimensional gel electrophoresis.

Total cellular proteins from mouse C3H10T1/2 fibroblasts were compared by two-dimensional (2-D) gel electrophoresis after radiolabeling with [35S]methionine (35S-Met) or 14C-amino acids (14C-AA). 35S-Met labeling of protein was three to four times greater than 14C-AA incorporation over a 24 h period. Automated comparative analysis of replicate fluorographs after 6, 12, and 24 h of labeling showed considerable homology between radiolabeling methods. More than 88% percent of 35S-Met and 14C-AA-labeled proteins were common at each time point. However, the total number of 35S-Met-labeled proteins dropped from 6 to 24 h while the number of 14C-AA-labeled proteins increased. Additionally, twenty-one proteins were uniquely labeled by 14C-AA that were not detectable by 35S-Met over the labeling period. Densitometric analysis showed that several 35S-Met and 14C-AA-labeled proteins exhibited time-related differences in radiolabel incorporation while most proteins remained relatively constant. Protein patterns of silver-stained gels from 6 to 24 h were highly registered and showed few qualitative differences. Proteins detected in radiolabeled gels were generally, but not always, found in silver-stained gels. Thus, 35S-Met appears better suited for short-term radiolabeling of cellular protein while more comprehensive labeling of protein occurs with 14C-AA during prolonged incubation of cell cultures under present experimental conditions.     

QSAR modeling of in vitro inhibition of cytochrome P450 3A4

We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drug-enzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.