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Analytical and Bioanalytical Chemistry (v.359, #1)
Combinatorial chemistry by C. von dem Bussche-Hünnefeld; F. Balkenhohl; A. Lansky; C. Zechel (pp. 3-9).
Rapid progress in molecular biology and the resulting ability to determine the activity of new compounds extremely efficiently have led to an enormously increased demand for test substances which cannot be satisfied by conventional synthesis methods. Combinatorial chemistry is a method that enables the efficient generation of large numbers of structurally diverse products. These products can be obtained as single compounds or in the form of defined mixtures. The synthesis is performed according to combinatorial principles (“produce all possible combinations of the reactants used”). The techniques and methods applied in combinatorial synthesis give rise to analytical problems: monitoring of reactions that take place on solid supports, structure elucidation with only minute amounts of material available or the characterization of substance mixtures. Examples from the authors’ laboratory illustrate how some of these problems can be approached.
MS-Pep: a computer program for the interpretation of mass spectra of peptide libraries by S. Kienle; K.-H. Wiesmüller; J. Brünjes; J. W. Metzger; G. Jung (pp. 10-14).
Electrospray mass spectrometry (ESI-MS) is an established method for the qualitative analysis of synthetic peptide libraries and combinatorial mixtures or collections of small organic compounds. However, the calculation of the mass distribution of even small peptide mixtures is a time-consuming and error-proned task. Therefore, the computer program MS-Pep has been developed, which calculates the masses of expected peptides, byproducts and the mass distributions of peptide libraries.
Label free binding assay with spectroscopic detection for pharmaceutical screening by M. Rothmund; Armin Schütz; Andreas Brecht; Günter Gauglitz; Günther Berthel; Dieter Gräfe (pp. 15-22).
Many therapeutic drugs exert their effects by interaction with well defined molecular targets. Increasing knowledge in molecular biology allows identification of more and more molecular key compounds and in consequence a molecular approach to disease and therapy. As binding of drugs to their target compounds is a key event, binding assays with an appropriate target molecule are useful means for primary screening of novel substances. We have investigated the potential of thin film interference spectroscopy (RIFS) as a label free detection method for pharmaceutical screening in a binding inhibition assay. To meet the throughput requirements in pharmaceutical screening a parallel detection system based on imaging spectroscopy was constructed. Thrombin/thrombin inhibitor interaction was investigated as a model system. The thin film transducer was covalently modified with a thrombin inhibitor. Specific binding of thrombin and binding inhibition by inhibitor compounds could be observed. A test cycle of less than 10 min could be reached. The parallel setup allows the simultaneous detection of 96 binding curves and can reach a throughput of more than 106 samples per year.
MOLecular structure GENeration with MOLGEN, new features and future developments by C. Benecke; T. Grüner; A. Kerber; R. Laue; T. Wieland (pp. 23-32).
MOLGEN is a computer program system which is designed for generating molecular graphs fast, redundancy free and exhaustively. In the present paper we describe its basic features, new features of the current release MOLGEN 3.5, and future developments which provide considerable improvements and extensions.
CSEARCH-STEREO: A new generation of NMR database systems allowing three-dimensional spectrum prediction by V. Schütz; V. Purtuc; S. Felsinger; W. Robien (pp. 33-41).
A new method for spectrum prediction is presented permitting incorporation of stereochemical features, which highly improves the quality of the obtained chemical shift values. The method is based on comparison of the query-structure with a reference library of ring skeletons, so that stereochemical interactions can be counted. The number of stereochemical interactions obtained over a five-bond sphere is used to produce a three-dimensional HOSE-code leading to a more accurate spectrum prediction. The advantages of this new concept will be discussed using examples from natural product chemistry.
Case studies of CSEARCH supported structure elucidation strategies: lupeol and a new germacrane derivative by Christoph Seger; Brigitte Jandl; Günter Brader; Wolfgang Robien; Otmar Hofer; Harald Greger (pp. 42-45).
The NMR based structure elucidation of secondary natural products can be supported by the CSEARCH database system. In the case of the triterpene lupeol the correct identification was performed without further experiments. The structure proposal for the new germacrane derivate hydroxygermacrene-D was proven by isomer generation and subsequent ranking of the eight isomers obtained by weighted spectrum estimation.
Modern strategies for PC-supported spectral analysis of 1D NMR data by U. Weber; A. Germanus; H. Thiele (pp. 46-49).
Analysis of high-resolution NMR spectra elucidation has been known for many years. Hard-and software development now permits the implementation of such programs on personal computers. The structural information hidden in complex proton NMR spectra becomes easily accessible by using graphical user interfaces and direct data exchange between programs. A new mode has been implemented in 1D WIN-NMR to support the analysis of multiplet patterns with first order rules. Structure display, direct export mechanisms to the simulation program WIN-DAISY, and an archiving possibility complete the state-of-the-art data analysis. Some practical examples are given.
Finding the 3D structure of a molecule in its IR spectrum by J. Gasteiger; J. Schuur; P. Selzer; L. Steinhauer; V. Steinhauer (pp. 50-55).
Based on a novel representation of the three-dimensional structure of molecules, the relationships between compounds and their infrared spectra are condensed into a counterpropagation network. Such a network can be used for the simulation of an infrared spectrum and thus provide infrared spectra for candidates in structure identification and elucidation problems. On the other hand, the counterpropagation network can also provide the three-dimensional structure of a compound on input of its infrared spectrum.
Derivation of substructures from infrared band shapes by fuzzy logic and partial cross correlation functions by F. Ehrentreich (pp. 56-60).
For the analysis of infrared spectroscopic bands and complex patterns partial cross correlation functions of a sample spectrum with reference spectra are calculated. The chosen ranges of the spectra are based on empirical knowledge of infrared spectrum structure correlations. The normalised maxima of the partial cross correlation functions are interpreted as fuzzy truth values and are combined by fuzzy logical operators. By application of that procedure larger common substructures will be derived from the reference spectra than by a maximum common substructure search based on the complete spectra.
Application of factor analysis in EDXRF by K. Molt; R. Schramm (pp. 61-66).
The application of factor analysis in EDXRF as a method for evaluation of elemental concentrations and calculation of net peak areas is demonstrated in two examples. A quantitative PCR-analysis of sulphur interfered with by molybdenum could be performed by using the XRF-spectra as input with a standard error of analysis (SEA) below 0.2 mg/g for aqueous and 3.6 mg/g for solid samples. By using PCR-predicted net peak areas as input for the empirical evaluation method developed by Lucas-Tooth and Price, the SEA for solid samples could be decreased to 2.3 mg/g. The comparison of PCR to PLS showed no significant difference.
How safe are NIR-library search systems? Information-theoretical and practical aspects by Karl Molt (pp. 67-73).
In chemical and pharmaceutical industries NIR-spectrometric methods are used in quality control laboratories to verify the identity of products and raw materials. However many analytical chemists are not sure how to estimate or even discuss the reliability and security of such systems. In this paper a simple information theoretical concept is applied to describe the uncertainty and other statistical properties of spectrometric and qualitative analytical methods in general.
In-line process monitoring on polymer melts by NIR-spectroscopy by D. Fischer; T. Bayer; K.-J. Eichhorn; M. Otto (pp. 74-77).
The application of near-infrared (NIR) spectroscopy to continuous monitoring of extrusion processes of polymers was demonstrated. NIR probes were adapted to the extruder outlet. The connection between probe and extruder was realized through a fiber-optic cable. The measurements utilized transmission or diffuse reflectance modes. Quantitative analysis was carried out using the chemometric methods of Partial Least Squares (PLS) and Principle Component Regression (PCR). Subjects of our investigations were the quantification of the composition of polymer blends (polypropylene/ethylene vinyl acetate copolymer) and the quantification of content of filler in polymer matrices (polypropylene/pulverized chalk) in the range of weight concentrations from 0 to 40%. The results show that NIR spectroscopy is suitable for quantitative in-line and real-time analysis of polymers.
Enhancing calibration models for non-invasive near-infrared spectroscopical blood glucose determination by C. Fischbacher; K.-U. Jagemann; K. Danzer; U. A. Müller; L. Papenkordt; J. Schüler (pp. 78-82).
Partial least-squares regression (PLS) and radial basis function (RBF) networks are used to compute calibration models for non-invasive blood glucose determination by NIR diffuse reflectance spectroscopy. A model computation shows that even extremely small deviations of the spectra induce increased prediction errors. Since the spectral contribution of blood glucose is much smaller than deviations resulting from the non-invasive measuring process a method based on Pearson’s correlation coefficient can be used for evaluating the quality of the recorded spectra during the prediction step. Another method is based on the leverage values from the hat matrix of the RBF network. Both methods lead to a significant decrease in prediction error.
Ex-vivo determination of blood glucose by microdialysis in combination with infrared attenuated total reflection spectroscopy by H. M. Heise; A. Bittner; T. Koschinsky; F. A. Gries (pp. 83-87).
Several biosensors have been developed for continuous monitoring of human blood glucose, which is desirable for insulin-dependent diabetic patients. Developments in the field of quantitative assays using infrared attenuated total reflection spectroscopy allow the determination of metabolites at low concentrations. The microdialysis technique can provide a continuous sampling of extracellular body fluids. As only compounds of low molecular weight are passed on, infrared spectrometric quantitation is eased considerably. Samples were obtained by microdialysis of human blood plasma and aqueous glucose solutions. Multivariate calibration by partial least-squares was evaluated for its analytical performance in ex-vivo blood glucose monitoring. Mean squared prediction errors obtained by cross validation were 5.4 mg/dL for dialysate samples from different patients and 1.3 mg/ dL for dialysates from glucose solutions. Further investigations were carried out to achieve miniaturization of the measuring and detection device.
Estimation of partition coefficients of organic compounds: local database modeling with uniform-length structure descriptors by Martin Junghans; E. Pretsch (pp. 88-92).
Octanol-water partition coefficients are predicted by building local models in a database. The structure space is spanned by uniform-length molecular descriptors derived from connectivity or three-dimensional structure, and from the occurrence of selected substructures. Individual models are derived for each structure cluster. In this contribution, various structure representations, clustering algorithms and mathematical models are investigated and the most appropriate procedure is selected.
Rapid and reliable spectral variable selection for statistical calibrations based on PLS-regression vector choices by H. M. Heise; A. Bittner (pp. 93-99).
The optimum number of spectral variables necessary for analytical spectroscopy is still a subject of debate. For sensor applications using miniaturized instrumentation, a small set of significant wavelengths with robust predictive performance is especially appreciated. A fast procedure is proposed, based on pairwise selection of spectral variables suggested by the weights of the optimum PLS-regression vector. The performance of multiple linear regression models based on such choices was similar to, and sometimes improved on full spectrum based modeling. Several examples from clinical studies of blood substrate assays using attenuated total reflection infrared spectroscopy of biofluids are presented.
Classical and modern algorithms for the evaluation of data from sensor-arrays by J. Seemann; F.-R. Rapp; A. Zell; G. Gauglitz (pp. 100-106).
Sensors have found wide application in process control, environmental analysis, and other analytical problems in recent years. Optical sensor arrays can be used to monitor organic solvent vapour mixtures by use of reflectometric interference spectroscopy. Lack in selectivity of the sensitive polymer films requires multivariate algorithms for evaluation. Two major aspects are of interest: the random error of calibration and the interpretation of the influence of a single sensor in an array with redundant information. Due to the partial selectivity of the different sensitive layers, non-linearities, cross-sensitivities, and differences in sensitivity, the selection of the most suitable sensitive polymer layers is not trivial. Model based algorithms allow the interpretation of variables whereas the model free algorithms provide better results concerning the random error of calibration. We choose the pruning algorithm to optimize a neural network topology in order to obtain the qualitative information on the sensor elements from the remaining links between the input layer and the hidden layer. We compare these results to the ones obtained for linear and non-linear PLS1 by partial least squares (PLS1) and calculate the errors for the calibration.
Enantioseparation of four-membered rings by gas chromatography; an overview by B. Koppenhoefer; Ulrich Epperlein; Marc Schwierskott (pp. 107-114).
The separation of enantiomers by gas chromatography on a chiral stationary phase is stored and conveniently retrieved in the molecular database Chirbase/GC. According to the present information content (version 3/96), a great variety of analytes has been published in several hundred journals. A selected review is given on 364 enantiomer separations of 102 different molecules containing at least one four-membered saturated carbocyclic ring. Factors determining the degree of enantioseparation are outlined and analyzed.
Intermolecular potentials and force constants from ab initio energies – Application to the N-H…O=C hydrogen bonds in formamide dimers by P. Bleckmann; P. Breitenbach; K. U. Dickhut; D. Keller; C. Schwittek (pp. 115-120).
The ab initio energies and force constants of 38 geometrically optimized formamide dimers which differ in the lengths of the hydrogen bonds, are evaluated using the program GAUSSIAN 90 with the 6–31G** basis set. A potential energy function was fitted simultaneously to the dimerization energies (including vibrational energy contributions to association energies) and the force constants of the N-H…O=C bridge. As an application, the broadening of the signals in vibrational spectra of liquid formamide was simulated by a superposition of spectra of different formamide oligomers.