Specimen position effects on energy shifts and signal intensity in a single-stage cylindrical-mirror analyzer

Peak-height changes and energy shifts associated with small (Δx = 0.1 mm) changes in specimen position in a single-stage cylindrical-mirror analyzer have been investigated. A specimen position for optimum signal strength is found experimentally and is predicted from theoretical calculations. An exact theoretical expression for signal intensity is presented in integral form. The integral has been evaluated numerically for finite aperture dimensions. It is found that the position dependence of signal intensity is a result of the finite size of the exit aperture and is not related to emission at the specimen or geometry of entrance aperture.     

Natural Product Inhibition and Enzyme Kinetics Related to Phylogenetic Characterization for Bacterial Peptidyl-tRNA Hydrolase 1

With the relentless development of drug resistance and re-emergence of many pathogenic bacteria, the need for new antibiotics and new antibiotic targets is urgent and growing. Bacterial peptidyl-tRNA hydrolase, Pth1, is emerging as a promising new target for antibiotic development. From the conserved core and high degree of structural similarity, broad-spectrum inhibition is postulated. However, Pth1 small-molecule inhibition is still in the earliest stages. Focusing on pathogenic bacteria, herein we report the phylogenetic classification of Pth1 and natural product inhibition spanning phylogenetic space. While broad-spectrum inhibition is found, narrow-spectrum and even potentially clade-specific inhibition is more frequently observed. Additionally reported are enzyme kinetics and general in vitro Pth1 solubility that follow phylogenetic boundaries along with identification of key residues in the gate loop region that appear to govern both. The studies presented here demonstrate the sizeable potential for small-molecule inhibition of Pth1, improve understanding of Pth enzymes, and advance Pth1 as a much-needed novel antibiotic target.     

Electrostatics of a point charge between intersecting planes: exact solutions and method of images

In this work, the authors present a commonly used example in electrostatics that could be solved exactly in a conventional manner, yet expressed in a compact form, and simultaneously work out special cases using the method of images. Then, by plotting the potentials and electric fields obtained from these two methods, the authors demonstrate that these two methods provide identical solutions. Furthermore, a number of sum rules are deduced based on the arguments that these two methods should also give the same induced charge, and force.     

The strength of glass

Large differences exist between the theoretical and experimental values of the mechanical strength of solids. Features of this phenomenon for glass are outlined together with a review of the current, incomplete explanation.     

Direct enantioselective Brønsted acid catalyzed N-acyliminium cyclization cascades of tryptamines and ketoacids

A direct enantio- and diastereoselective N-acyliminium cyclization cascade through chiral phosphoric acid catalyzed condensation of tryptamines with γ- and δ-ketoacid derivatives to provide architecturally complex heterocycles has been developed. The reaction is technically simple to perform, atom-efficient, and broad in scope. Employing 10 mol % of (R)-BINOL derived chiral phosphoric acids in refluxing toluene allowed the polycyclic product materials to be generated in good yields (53-99%) and moderate to high enantioselectivities (68-98% ee).     

Drug-like density: a method of quantifying the "bindability" of a protein target based on a very large set of pockets and drug-like ligands from the Protein Data Bank

One approach to estimating the "chemical tractability" of a candidate protein target where we know the atomic resolution structure is to examine the physical properties of potential binding sites. A number of other workers have addressed this issue. We characterize ~290,000 "pockets" from ~42,000 protein crystal structures in terms of a three parameter "pocket space": volume, buriedness, and hydrophobicity. A metric DLID (drug-like density) measures how likely a pocket is to bind a drug-like molecule. This is calculated from the count of other pockets in its local neighborhood in pocket space that contain drug-like cocrystallized ligands and the count of total pockets in the neighborhood. Surprisingly, despite being defined locally, a global trend in DLID can be predicted by a simple linear regression on log(volume), buriedness, and hydrophobicity. Two levels of simplification are necessary to relate the DLID of individual pockets to "targets": taking the best DLID per Protein Data Bank (PDB) entry (because any given crystal structure can have many pockets), and taking the median DLID over all PDB entries for the same target (because different crystal structures of the same protein can vary because of artifacts and real conformational changes). We can show that median DLIDs for targets that are detectably homologous in sequence are reasonably similar and that median DLIDs correlate with the "druggability" estimate of Cheng et al. (Nature Biotechnology 2007, 25, 71-75).