Carbon-13 nuclear magnetic resonance studies of creatine,creatinine and some of their analogs

Creatine (N-methyl-N-amidinoglycine), creatinine (1-methyl-2-aminoimidazolin-4-one) and a series of 38 of their close structural analogs have been examined using natural abundance ¹³C NMR spectroscopy at 25.16 MHz. Both proton-coupled and proton noise-decoupled spectra were recorded. Unequivocal assignments of the carbon resonances could be made in the vast majority of cases. Both ¹³C NMR chemical shifts and ¹J(CH) values can be used to characterize and to differentiate readily between analogs of creatine and analogs of creatinine. For example, the ¹J(CH) coupling constants for the α-carbons of the acyclic creatine analogs were all in the 140–142 Hz range, whereas the corresponding coupling constants for the related, cyclized creatinine analogs were all in the 150–152 Hz range.     

Computational validation of the importance of absolute stereochemistry in virtual screening

Consideration of stereochemistry early in the identification and optimization of lead compounds can improve the efficiency and efficacy of the drug discovery process and reduce the time spent on subsequent drug development. These improvements can result by focusing on specific enantiomers that have the desired potential therapeutic effect (eutomers), while removing from consideration enantiomers that may have no, or even undesirable, effects (distomers). A virtual screening campaign that correctly takes stereochemical information into account can, in theory, be utilized to provide information about the relative binding affinities of enantiomers. Thus, the proper enumeration of the relevant stereoisomers in general, and enantiomeric pairs in particular, of chiral compounds is crucial if one is to use virtual screening as an effective drug discovery tool. As is obvious, in cases where no stereochemical information is provided for chiral compounds in a 2D chemical database, then each possible stereoisomer should be generated for construction of the subsequent 3D database to be used for virtual screening. However, acute problems can arise in 3D database construction when relative stereochemistry is encoded in a 2D database for a chiral compound containing multiple stereogenic atoms but absolute stereochemistry is not implied. In this case, we report that generation of enantiomeric pairs is imperative in database development if one is to obtain accurate docking results. A study is described on the impact of the neglect of enantiomeric pairs on virtual screening using the human homolog of murine double minute 2 (MDM2) protein, the product of a proto-oncogene, as the target. Docking in MDM2 with GLIDE 4.0 was performed using the NCI Diversity Set 3D database and, for comparison, a set of enantiomers we created corresponding to mirror image structures of the single enantiomers of chiral compounds present in the NCI Diversity Set. Our results demonstrate that potential lead candidates may be overlooked when databases contain 3D structures representing only a single enantiomer of racemic chiral compounds.     

Height Fluctuations in the Honeycomb Dimer Model

We study a model of random surfaces arising in the dimer model on the honeycomb lattice. For a fixed “wire frame” boundary condition, as the lattice spacing ϵ → 0, Cohn, Kenyon and Propp [3] showed the almost sure convergence of a random surface to a non-random limit shape Σ₀. In [12], Okounkov and the author showed how to parametrize the limit shapes in terms of analytic functions, in particular constructing a natural conformal structure on them. We show here that when Σ₀ has no facets, for a family of boundary conditions approximating the wire frame, the large-scale surface fluctuations (height fluctuations) about Σ₀ converge as ϵ → 0 to a Gaussian free field for the above conformal structure. We also show that the local statistics of the fluctuations near a given point x are, as conjectured in [3], given by the unique ergodic Gibbs measure (on plane configurations) whose slope is the slope of the tangent plane of Σ₀ at x.     

Design-of-experiment optimization of exhaled breath condensate analysis using a miniature differential mobility spectrometer (DMS)

Analytical instruments that can measure small amounts of chemicals in complicated biological samples are often useful as diagnostic tools. However, it can be challenging to optimize these sensors using actual clinical samples, given the heterogeneous background and composition of the test materials. Here we use gas chromatography-differential mobility spectrometry (GC/DMS) to analyze the chemical content of human exhaled breath condensate (EBC). Ultimately, this system can be used for non-invasive disease diagnostics. Many parameters can be adjusted within this instrument system, and we implemented a factorial design-of-experiments to systematically test several combinations of parameter settings while concurrently analyzing effects and interactions.We examined four parameters that affect sensitivity and detection for our instrument, requiring a 2⁴ factorial design. We optimized sensor function using EBC samples spiked with acetone, a known clinical biomarker in breath. Two outputs were recorded for each experiment combination: number of chemicals detected, and the amplitude of acetone signal. Our goal is to find the best parameter combination that yields the highest acetone peak while also preserving the largest number of other chemical peaks in the spectra. By optimizing the system, we can conduct further clinical experiments with our sensor more efficiently and accurately.     

Modular and reconfigurable gas chromatography/differential mobility spectrometry (GC/DMS) package for detection of volatile organic compounds (VOCs)

Due to the versatility of present day microcontroller boards and open source development environments, new analytical chemistry devices can now be built outside of large industry and instead within smaller individual groups. While there are a wide range of commercial devices available for detecting and identifying volatile organic compounds (VOCs), most of these devices use their own proprietary software and complex custom electronics, making modifications or reconfiguration of the systems challenging. The development of microprocessors for general use, such as the Arduino prototyping platform, now enables custom chemical analysis instrumentation. We have created an example system using commercially available parts, centered around on differential mobility spectrometer (DMS) device. The Modular Reconfigurable Gas Chromatography - Differential Mobility Spectrometry package (MR-GC-DMS) has swappable components allowing it to be quickly reconfigured for specific application purposes as well as broad, generic use. The MR-GC-DMS has a custom user-friendly graphical user interface (GUI) and precisely tuned proportional-integral-derivative controller (PID) feedback control system managing individual temperature-sensitive components. Accurate temperature control programmed into the microcontroller greatly increases repeatability and system performance. Together, this open-source platform enables researchers to quickly combine DMS devices in customized configurations for new chemical sensing applications.     

Benzimidazole-Derived ATP Analogues as Potential Glutamine Synthetase Inhibitors

A series of mono- and dihydroxyalkyl- and -alkyloxybenzimidazoles and their phosphorylated derivatives have been prepared as adenosine triphoshate analogues for investigation as potential M. Tb. glutamine synthetase inhibitors.     

Development of the resolution theory for electrophoretic exclusion

Electrophoretic exclusion, a technique that differentiates species in bulk solution near a channel entrance, has been demonstrated on benchtop and microdevice designs. In these systems, separation occurs when the electrophoretic velocity of one species is greater than the opposing hydrodynamic flow, while the velocity of the other species is less than that flow. Although exclusion has been demonstrated in multiple systems for a range of analytes, a theoretical assessment of resolution has not been addressed. To compare the results of these calculations to traditional techniques, the performance is expressed in terms of smallest difference in electrophoretic mobilities that can be completely separated (R = 1.5). The calculations indicate that closest resolvable species (Δμ_min) differ by approximately 10^?13 m²/Vs and peak capacity (n_c) is 1000. Published experimental data were compared to these calculated results.     

Biased Random Walks, Lyapunov Functions, and Stochastic Analysis of Best Fit Bin Packing

We study the average case performance of the Best Fit algorithm for on-line bin packing under the distributionU{j, k}, in which the item sizes are uniformly distributed in the discrete range {1/k, 2/k,…,j/k}. Our main result is that, in the casej = k − 2, the expected waste for an infinite stream of items remains bounded. This settles an open problem posed by Coffmanet al.[[4]]. It is also the first result which involves a detailed analysis of the infinite multidimensional Markov chain underlying the algorithm.