bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinguishing Atom Differences in a Molecular Graph Shape Index
Authors: Kier Lemont B.
Published: October 2006

The molecular shape index, previously described, has been extended to take into account the size differences among heteroatoms and carbon atoms in different valence states. In the algorithm for the shape index, 2K, calculated as a function of the non‐hydrogen atom count, the count value of non‐C sp3 atoms is modified by a term α. The value of α is derived from the covalent radius of an atom relative to the radius of C sp3. Several examples of the use of the atom‐specified shape index, 2Kα, in biological studies are presented.
Quantitative Structure‐Activity Relationships on MAO Substrates by Means of Quantum Chemical Properties
Authors: Sanz F. , Martiń M. , Lapeña F. , Manaut F.
Published: October 2006

The structural and electrostatic requirements for the two types of monoamine oxidase (MAO) activity are quantitatively studied using similarity coefficients between the electron density and the molecular electrostatic potential (MEP) distributions of a set of substrates.

For the comparison of electron density distributions, the RXY similarity coefficient is used. In the case of MEP a new similarity coefficient is defined.

Correlations between these coefficients and the experimental activities are studied and the results are consistent with previous ones. This shows the interest of this two parameters in QSAR studies.
Chance Factors in Nonparametric Linear Discriminant Studies
Authors: Stouch Terry R. , Jurs Peter C.
Published: October 2006

Studies were performed to determine if the screening of large pools of prospective variables could lead to fortuitous improvements in the classification success rates provided by nonparametric linear discriminants. These studies parallel earlier work by Topliss and Edwards on regression analysis. It was found that fortuitous increases do occur, but could probably be kept low if the number of examined variables is kept below one‐half the number of observations.
Structure‐Molar Refraction Relationships of Alkylsilanes Using Empirically‐Modified First Order Molecular Connectivity Indices
Authors: Kupchik Eugene J.
Published: October 2006

Two empirically‐modified first order molecular connectivity indices, which reflect either the larger covalent radius of silicon compared to carbon or the longer silicon‐carbon bond length compared to the carbon‐carbon bond length, were calculated for 115 alkylsilanes. The correlation of molar refraction with these empirically‐modified first order molecular connectivity indices was found to be excellent. It is shown that these empirically‐modified molecular connectivity indices give a significantly more satisfactory prediction of molar refraction for a mixed set of alkanes and alkylsilanes than does the simple first order molecular connectivity index or the first order molecular connectivity index derived from molar refraction data.
Three‐Dimensional Quantitative Structure‐Activity Relationships I. General Approach to the Pharmacophore Model Validation
Authors: Motoc Ioan , Dammkoehler Richard A. , Mayer Dorica , Labanowski Jan
Published: October 2006

A conceptually and computationally integrated approach to pharmacophore model validation is discussed at length. It allows one, for the first time, to address the question of pharmacophore existence and assessment of its uniqueness in a rigorous and quantitative manner. The approach has been effectively applied to the analysis of seventeen structurally diverse potent inhibitors of angiotensin converting enzyme and the resultant pharmacophore greatly refines the previously suggested models.
Inclusion of Symmetry as a Shape Attribute in Kappa Index Analysis
Authors: Kier Lemont B.
Published: October 2006

The molecular shape attribute of symmetry is introduced as a supplement to the shape attributes encoded by the kappa values. This attribute is indexed by the Shannon equation for information content and is designated as 0κ within the framework of multiple path, path and atom counts to derive the kappa values. A new procedure is introduced to calculate a label characterizing the uniqueness or equivalence of atoms in a molecule using the connection matrix. This label, called the relative topological state, is used in the Shannon equation to calculate the information content or 0κ. Two examples illustrate the utility of 0κ along with other kappa values to encode attributes of molecular shape influencing physical and biological properties.
Hydrophobic Properties of Chromones and Flavones. Relationships Between Octanol/Water Partition Coefficients and RP‐HPLC Capacity Factors
Authors: Recanatini Maurizio
Published: October 2006

The octanol/water partition coefficient (P) and the RP‐HPLC capacity factors (k′) at four different concentrations of organic modifier (methanol) in the mobile phase have been measured. The observed log P values of the polar substituted compounds show good consistency, if the interactions among the polar groups are taken into account on the basis of the Leo‐Fujita theory. Log P and log k′ are linearly correlated at the four methanol concentrations examined and at the extrapolated 0% methanol concentration. The phenolic compounds deviate from the correlation and this is recognized as a characteristic behaviour of the C‐18/ MeOH‐H2O chromatographic system.
A Substituent Steric Effect Index Based on the Molecular Graph
Authors: Kier Lemont B.
Published: October 2006

Three graph‐based indexes of molecular shape have been found to correlate well with the Taft steric indexes, Es, for electron influence‐free alkyl groups and ten symmetric‐top groups used by Charton to compute a Van der Waals radius‐based index, v. The equation model includes the 1kα, and 3Kα, shape indexes and the 0k index equivalent to the Shannon information content per molecule. This later index encodes the group symmetry. The equation model is simplified to the expression ≈︁ = 2k ‐ 3kα ‐ 0k where Xi (≈︁) is proposed as a graph‐based shape index encoding the steric influence of a group.
Multivariate Characterization of Amino Acids by Reversed Phase High Pressure Liquid Chromatography
Authors: Skagerberg Bert , Sjöström Michael , Wold Svante
Published: October 2006

The twenty coded and four non coded amino acids were multivariately characterized by HPLC. The retention times for dansyl derivatives of the amino acids in nine eluents on a reversed phase C18 column were used.

With the nine HPLC variables and five additional variables (molecular weight, pK‐COOH, pK‐NH2, pI and substituent van der Waals volume) comprizing the matrix X, two partial least squares projections to latent structures (PLS) models were developed for eighteen of the coded amino acids, with the previously developed principal properties (PP.s) z1 and z2 as single y‐variables. The PLS models described 90% and 87% of variance in z1 and z2 respectively. Values for z1 and z2 for the four non coded amino acids were predicted from their X‐data and the PLS models.
Systematic QSAR Procedures with Quantum Chemical Descriptors
Authors: Kikuchi Osamu
Published: October 2006

Systematic QSAR procedures with quantum chemical descriptors were described by showing practical calculations on the inhibition of thiopurine methyltransferase by benzoic acid derivatives. In the QSAR analysis, a large number of descriptors relating to reactivity and interaction efficiency are handled, and the collinearities inherently involved among them should be removed to get the stable regression equations. Collinearity was detected by the A value which is the sum of the reciprocals of the eigenvalues of correlation matrix of descriptors divided by the number of descriptors in the equation. In the method of evaluation of all possible equations, the candidate equations selected on the basis of the correlation coefficient with activity and/or predicted sum of square should be examined one by one by the A testing. In the stepwise methods, noncollinear descriptor set is required. The collinearity between two descriptors was removed by a simple method, deleting one of the two descriptors whose correlation is large. It was recommended that the A testing routine was introduced into each step to find out multicollinearity.
Molecular Modelling of the Active Site of Enkephalin‐Degrading Neutral Endopeptidase‐24.11 (Enkephalinase) An Active Site Model for Neutral Endopeptidase‐24.11
Authors: Andrews Peter R. , Iskander Magdy N. , Issa John , Reiss James A.
Published: October 2006

The active site regions of thermolysin (TLN) and carboxypeptidase A (CPA) are directly compared by superimposition of the published crystal structures of eight TLN/inhibitor complexes and four CPA‐inhibitor complexes. There is a remarkable similarity in the S′1 region of these two zinc metalloenzymes, and it is suggested that this may be a common feature among other enzymes of this class, including the enkephalin‐degrading neutral endopeptidase or “enkephalinase” (NEP‐24.11). Assuming this common feature, the possible geometry of the S′2 region of enkephalinase was determined by performing classical potential energy calculations on potent NEP‐24.11 inhibitors. The active conformation of these inhibitors was thus identified as similar to that found in the X‐ray crystal structure of TLN/inhibitor complexes. It is proposed that the active site region of TLN should serve as a reasonable model for that of NEP‐24.11. Extension of the model to the case of angiotensin‐converting enzyme (ACE) showed that this enzyme might have a similar S′1 region to the other three enzymes, and allowed further definition of the ACE model previously developed in our laboratory.
Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in Conventional QSAR Studies
Authors: Cramer Richard D. , Bunce Jeffrey D. , Patterson David E. , Frank Ildiko E.
Published: October 2006

To better evaluate, in the context of QSAR studies, new validation techniques such as bootstrapping and crossvalidation and the new analytic technique of partial least squares (PLS), seventeen QSAR results taken from nine recent publications were reexamined using these techniques. The results indicate that bootstrapping and crossvalidation are more powerful indicators of possible chance correlation than are the classical tests based on assumed normal independent distribution of variables. Although PLS will not detect all correlations existing within a set of data, its conservative behavior is particularly valuable when the candidate physicochemical descriptors are numerous and non‐orthogonal.
Structure — Molar Refraction Relationships of Alkylgermanes Using Molecular Connectivity
Authors: Kupchik Eugene J.
Published: October 2006

Correlation of molar refraction with the first order molecular connectivity index was found to be excellent for alkylgermanes of molecular formula GeCnH2n+4. The correlation was further improved by the use of either of two empirically‐modified first order molecular connectivity indices, which reflect either the larger covalent radius of germanium compared to carbon or the longer germanium‐carbon bond length compared to the carbon‐carbon bond length. Use of the empirically‐modified indices improves the prediction of molar refraction for a mixed set of alkanes and alkylgermanes and for a mixed set of alkanes, alkylsilanes, and alkylgermanes.
Hydrophobicity of Di‐ and Tripeptides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters
Authors: Akamatsu Miki , Yoshida Yohji , Nakamura Hideaki , Asao Masaaki , Iwamura Hajime , Fujita Toshio
Published: October 2006

After establishing experimental conditions to obtain a reliable partition ratio, P', we measured the value of 59 di‐ and tripeptides composed of amino acids having unionizable side chains in a 1‐octanol/pH 7.0 aqueous phosphate buffer system in order to approximate the true partition coefficient. We then formulated an equation correlating the variations of log P' (pH 7) among peptides with free‐energy‐related physicochemical parameters for the side chain substituents and substructures. The log P' value of di‐ and tripeptides is governed by the sum of the hydrophobicity of the peptide backbone and side chains as well as by the steric effect of side chain substituents on the relative solvation of backbone and terminal functional groups. For peptides containing amino acids with polar side chains, the log P' value is higher than that predicted by these effects. The difference is larger as the polar heteroatom in side chains gets closer to the backbone. This may correspond to the “polar proximity factor” for reductions of hydrophilicity observed when polar groups are crowded together. For the side chain of serine and threonine, the difference is even higher than that expected by the polar proximity effect, presumably due to intramolecular hydrogen bond formation.
QSAR and Binding Model for Inhibition of Rat Liver Catechol‐O‐Methyl‐Transferase by 1,5‐Substituted‐3,4‐Dihydroxybenzenes
Authors: Taskinen Jyrki , Vidgren Jukka , Ovaska Martti , Backström Reijo , Pippuri Aino , Nissinen Erkki
Published: October 2006

Quantitative structure‐activity analysis was carried out for in vitro inhibition of rat liver catechol‐O‐methyl‐transferase by a series of 1,5‐substituted‐3,4‐dihydroxybenzenes. Linear regression analysis showed high correlation of inhibitory activity with both empirical electronic substituent parameters and quantum chemical descriptors. The combined effect of both substituents on lowering the pKa values of catechol hydroxyls and the energy of the lowest unoccupied molecular orbital appeared to be the most important determinant of increasing activity. Both substituents seemed to be also directly involved in binding. Hydrophobicity of the substituent at position 1 and the electronic structure of the substituent at position 5 were correlated with activity. A model for binding interactions of inhibitors was postulated on the basis of the QSAR equations derived.
Electron Affinity/Radiosensitizing Activity Relationship for Quaternary 5‐Nitroimidazole Derivatives. Quantum Chemical QSAR
Authors: Santos Lucia , Pilar Cornago M. , Izquierdo M. Cruz , Consuelo Lopez‐Zumel M. , Smeyers Y. G.
Published: October 2006

The electron affinity of five new synthetised quaternary 5‐nitroimidazole derivatives was evaluated by means of quantum mechanical CNDO/S calculations and by polarographic measurements. The final aim of these evaluations was to correlate the electron affinity of the products with their previously tested radiosensitizing efficiencies, in order to elucidate the classification of these products as electroaffinic radiosensitizers, in the same way as many other nitroimidazole compounds. Results from both the experimental and theoretical methods give an equally good evaluation of the product electron affinity. An exponential correlation between the LUMO energy values of the neutral molecular structures and the cellular radiosensitizing efficiencies (D.M.F.) of the products was obtained; and this result enables these quaternary 5‐nitroimidazole derivatives to be classified as electroaffinic radiosensitizers.
Molecular Structure Description by Segmentation of Atomic Score Spaces (SASS)
Authors: Alsberg Bjørn , Esbensen Kim
Published: October 2006

Molecular structure is represented as segmented volume elements of 3‐D principal component score spaces of molecules. Clonidine conformations were analysed by principal component analysis (PCA) and their corresponding conformational energies were regressed on segmented PCA score pattern for each conformation. Conformational energy is interpreted as the “activity” of these molecular conformations. The resulting model is able to predict the energy also for other conformations not included in the calibration. We suggest that segmented atomic score spaces (SASS) can be a valuable tool in quantitative structure‐activity relationship (QSAR) studies.
DARC Computer Aided Design in Anticholinergic Research
Authors: Mercier Christiane , Trouiller Gérard , Dubois Jacques‐Emile
Published: October 2006

A dynamic method for the setting up and computer‐aided handling of an “ANTICHOLINERGIC” data bank has been designed in order to rationalize the planning of pharmacological and chemical experimentation with a view to optimizing series known to be active. The DARC Computer Aided Design method has been employed to specify the pharmacological profile of certain tests, to reduce the cost of experimentation and to discover new structures either with high central anticholinergic activity or with greater peripheral than central anticholinergic activity. The structural and pharmacological data are reported for more than 60 3‐thienyl aminoalcohol glycolates.
MD simulations in Pseudo‐Particle Fluids: Applications to active‐site Protein Complexes
Authors: Kern Petra , Rognan Didier , Folkers Gerd
Published: October 2006

Truncated protein‐ligand active‐site complexes were studied by molecular dynamics simulations. Pseudo‐particles were used for the representation of the outer protein parts and the surrounding solvent. This pseudo‐particle approach was applied to the MD simulation of adenylate kinase wild type or mutant enzymes in complex with different ligands. For further validation of the method, the human leucocyte antigen HLA‐B27 was simulated in complex with three different nonapeptides. All molecular dynamics simulations were additionally compared with biochemical data. Despite the crude approximation of the outer protein parts and the solvent environment, differences in binding properties of the ligands could be observed and correlated to experiments.
Comparative Structure‐Affinity Relations by MTD for Binding of Cycloadenosine Monophosphate Derivatives to Protein Kinase Receptors
Authors: Mureşan Sorel , Jastorff Bernd , Kurunczi Ludovic , Simon Zeno
Published: October 2006

A “testkit” series of 27 derivatives of cAMP with various substituents in position 1, 2, 6 and 8 and within the purine cycle, thiophosphoric acid derivatives (with equatorial or axial S‐atom) also included, were used to map four receptor sites of the R‐subunit of cAMP dependent phosphokinases I and II, namely labile and stable receptors AI, BI, AII and BII. A QSAR by the MTD method was applied for the four series of activities, together with the relative nitrogen base hydrophobicity (lgKw), electric charge of the position 6‐substituent (qN) and an indicator variable (δ = 1 for equatorial thiophosphoric derivatives). Correlation coefficients between r = 0.836 and 0.948 were obtained and the reliability of QSAR results was tested by a cross validation‐like procedure. Characteristic steric features (concerning the effects of substituents in different nitrogen‐base positions) were separately obtained for each receptor. For AI and BI receptor there is a negatively charged receptor group interacting with substituents in position 6 of cAMP derivatives. BI and BII receptors are of a marked hydrophobic character. Thiophosphoric acid derivatives, especially those with equatorial S‐atom, have a decreased affinity for all four receptors. The results are compared with other QSAR studies of our group, concerning different series of cAMP derivatives.
SAR Models for Metabolic Activation: Stability of Organic Cation Intermediates
Authors: Mekenyan Ovanes G. , Veith Gilman D. , Bradbury Steven P. , Zaharieva Nora
Published: October 2006

Semi‐empirical methods for estimating the stability of organic cations through hydride abstraction or protonation were evaluated. To simulate hydride abstraction, stability was defined as the difference between the calculated enthalpies of the cations and the parent structures. Cations formed by protonation were compared to proton affinities by computing enthalpies of the conjugate acids and the corresponding bases. Semi‐empirical quantum chemical methods, including AM1, PM3 and MNDO hamiltonians, were used to evaluate their capability to model reaction enthalpies and estimate cation stability. All three methods were acceptable in estimating the stability of cations obtained by hydride abstraction. The correlation coefficients between computed stabilities from the three methods and measured stabilities ranged from 0.83 for MNDO to 0.92 for AMl. The AMl method was the only acceptable hamiltonian for estimating proton affinity for the studied chemicals. The correlation coefficient between measured and computed values was 0.89. The models for stability will be incorporated into larger QSAR activation models for estimating the probability of mutagenicity and tumor formation in risk assessments.
The μ Opioid Receptor Binding Pharmacophore Conformation of Ornithine Containing Cyclic β‐Casomorphin Analogues and Related Peptides
Authors: Brandt Wolfgang , Mrestani‐Klaus Carmen , Schinke Heiko , Neubert Klaus , Barth Alfred , Schmidt Ralf , Schiller Peter W. , Höltje Hans‐Dieter
Published: October 2006

Low energy conformers of both active and nearly inactive cyclic β‐casomorphin analogues, such as Tyr‐c[‐Orn‐X‐Pro‐Gly‐], Tyr‐c[‐Orn‐X‐D‐Pro‐Gly‐], Tyr‐c[‐D‐Orn‐X‐Pro‐Gly‐] and Tyr‐c[‐D‐Orn‐X‐D‐Pro‐Gly‐] (X=Phe or 2‐Nal) have been determined in a systematic conformational search using the TRIPOS force field. The obtained conformations were compared with a model based on structure(conformation)‐activity relationships for μ‐selective non‐peptide opiates and taking into consideration both conformational features and molecular electrostatic potentials. On the basis of these findings we were able to propose plausible pharmacophoric structures for the cyclic β‐casomorphins. These conformations were in close agreement with those determined in solution by 1H NMR spectroscopy. The pharmacophoric moieties contained in these structures are in a spatial disposition which allows them to interact with several proposed subsites of the μ‐receptor. These are an anionic site (area A) engaged in an electrostatic interaction with the protonated N‐terminus of the peptides, two hydrophobic sites (areas C and D) that are both occupied by aromatic rings (Tyr and Phe in the case of the peptides) and two hydrophilic receptor binding sites (areas B and F). In all peptides the N‐terminal tyrosine residue assumes a very similar conformation, permitting its interaction with receptor areas A, B and C. Furthermore, the intramolecular distance between the centroids of the Phe3 aromatic ring (interacting with area D) and the Tyr1 ring is about 10 to 11 Å. According to the model, a further receptor subsite designated as F interacts with the carbonyl of the D‐Orn2 residue and in the case of the morphiceptin analogues with the carbonyl group of either cisPro2 or Pro4. The array of proposed receptor subsites also accommodates various opiate alkaloids, several enkephalin analogues and the message domain of dermorphins and deltorphins. Furthermore, the model provides an explanation for the lack of activity observed with cyclic β‐casomorphin analogues containing L‐ornithine in the 2‐position of the peptide sequence. The similarity between the pharmacophore conformations of the opioid peptides and the non‐peptide opiates suggests that their mode of binding to the receptor may be similar.
QSAR Study of the Toxicity of Nitrobenzenes to Tetrahymena pyriformis
Authors: Dearden John C. , Cronin Mark T. D. , Schultz T. Wayne , Lin David T.
Published: October 2006

A QSAR analysis has been carried out of the toxicity of 47 mono‐substituted nitrobenzenes to the aquatic ciliate Tetrahymena pyriformis. The single most important parameter was the logarithm of the apparent partition coefficient (logD) at pH 7.35. 2‐ and 3‐derivatives yielded an excellent correlation of toxicity with log D, Swain‐Lupton field parameter and modulus of change of charge on the nitro group oxygen upon substitution. This is consistent with their behaving as pro‐electrophiles. 4‐derivatives, however, clearly had a different mode of action, with the best correlation being found with log D, molar refractivity and the Shannon index.
Structure‐Affinity Binding Relationships by Principal‐Component‐Regression Analysis of Anthraquinone Dyes
Authors: Timofei Simona , Kurunczi Ludovic , Schmidt Walter , Fabian Walter M. F. , Simon Zeno
Published: October 2006

Dye‐fibre binding was modelled by principal‐component‐regression analysis (PCRA) method for two series of 46, respectively 49 anthraquinone vat dyes. Robust equations with predictive modelling power were proposed for the correlations with structural parameters (r2 = 0.92 and s = 0.48, respectively r2 = 0.94 and s = 0.47). They indicated the presence of steric, electronic and hydrophobic effects in the dyeing process. PCRA allows to avoid the multicollinearity of the physicochemical descriptors, yielding better results as compared to those obtained from ordinary leastsquares analysis.
Parameter Based Methods for Compound Selection from Chemical Databases
Authors: Hudson Brian D. , Hyde Richard M. , Rahr Elizabeth , Wood John , Osman Julian
Published: October 2006

Two algorithms for the selection of subsets of compounds from chemical databases are presented and discussed. The first is designed to select representative subsets whilst the second is intended to select compounds which cover the available property space. Both make use of calculated physicochemical parameters in contrast to more common methods based on molecular fingerprints. This is an approach to molecular similarity which has proved successful in the past. The methods are illustrated with examples and discussed.
Exhaustive Conformational Searches for Superimposition of Acaricidal Compounds
Authors: Akagi Toshio , Takahashi Yoshimasa , Sasaki Shin‐Ichi
Published: October 2006

Three‐dimensional common structural features among three acaricidal compounds which inhibit respiratory complex I were investigated, assuming that they have a similar binding mode. The techniques of COMPASS (COMmon geometrical Pattern Search System) and “molecular field fitting” were employed and exhaustive conformational space searches were performed without any presumption. The results suggested that the “active conformations” of these compounds are non‐planar. Within each type a lone‐pair containing functional group on the heterocyclic ring as well as a hydrophobic region with a t‐butyl group overlapped well, despite the difference in size and chemical nature of the connecting bridge. Structure‐activity relationships of the compounds are explained successfully by the energy of the “active conformation”. The present study demonstrates the usefulness of the exhaustive conformational search to derive simultaneously the “active conformation” and the mode of superimposition.
Evolutionary Neural Networks in Quantitative Structure‐Activity Relationships of Dihydrofolate Reductase Inhibitors
Authors: Kyngäs Jari , Valjakka Jarkko
Published: October 2006

The evolutionary neural network (ENN) is a new system for modelling multifactor data. The strength of ENN's are that they can extract insignificant predictors, choose the size of the hidden layer and fine tune the parameters needed in training the network. We have used an ENN to predict the biological activities of Dihydrofolate Reductase Inhibitors. As a result, we found that evolutionary neural networks give more accurate predictions than statistical methods and feedforward neural networks.
Recent Success Stories Leading to Commercializable Bioactive Compounds with the Aid of Traditional QSAR Procedures
Authors: Fujita Toshio
Published: October 2006

New successful applications of the Hansch‐type traditional QSAR to key steps in designing novel bioactive compounds are reviewed. Studies for a benzhydrylbenzylpiperazine antimigraine agent (lomerizine), azole‐type agricultural fungicides (metconazole and ipconazole), and a biphenylyloxobutanoic acid antiinflammatory agent (flobufen) were taken as the examples. Structural optimizations were nicely made by using the QSAR information sometimes along with findings obtained from 3D molecular modelling studies and/or hypotheses proposed for metabolic fates. The two azole fungicides were launched in 1994. The antimigraine and antiinflammatory agents are expected to be commercialized soon.
Chemometric Study and Validation Strategies in the Structure‐Activity Relationships of New Cardiotonic Agents
Authors: Boggia Raffaella , Forina Michele , Fossa Paola , Mosti Luisa
Published: October 2006

Forty‐two molecules, thirty‐eight milrinone analogues, two lead compounds, amrinone and milrinone, and two commercial products have been studied using chemometrical techniques applied to thirty theoretical descriptors and two biological activities (each one at three different concentrations).

PLS Regression was applied both in the usual form PLS‐1, with one response variable, and as PLS‐2, with the contemporary study of more activities in the block of response variables.

Regression models (both with the original activities and with log and arctan transforms) were refined by progressive elimination of conformers and of non‐relevant predictors, one‐at‐a‐time, on the basis of the relevance in the regression equation. Different sorts of model refinement gave origin to four chemometrical strategies.

Special attention was deserved to the development of validation procedures for the regression analysis, in order to evaluate the true predictive ability of the refined models. The predictive optimization was based on cross‐validation. Complete validation using three sets (training, optimization, external) was applied in one of the strategies. Both optimization and validation were performed in different conditions in order to eliminate the possibility of chance correlation.

The severe validation procedures applied prevent underestimate of prediction error, frequently encountered when partial validation procedures are applied.

Only one biological activity at the highest concentration can be predicted from the theoretical descriptors with a reasonable prediction error, measured by cross‐validated explained variance. Only volume descriptors have a sure importance in the final regression model.
Nonlinear CoMFA using QPLS as a Novel 3D‐QSAR Approach
Authors: Hasegawa Kiyoshi , Kimura Toshiro , Funatsu Kimito
Published: October 2006

Comparative molecular field analysis (CoMFA) using partial least squares (PLS) is a popular method in 3D‐QSAR studies. Although CoMFA has been of general use, it is suboptimal or even useless when nonlinear relationships are observed between field variables and biological activity. Quadratic PLS (QPLS) developed by Wold et al. is an extension of PLS to deal with nonlinear chemical data. In this paper, it is demonstrated that QPLS can be applicable to the 3D field variables in CoMFA. The structure‐activity data of dihydrofolate reductase (DHFR) inhibitors were used as a test example. The resulting QPLS model gave high predictivity with only one component to explain the nonlinear relationships between the electrostatic field variables and inhibitory activity. The loading values of the QPLS model were plotted in 3D space and chemically reasonable contour maps were obtained in accordance with the previous multiple and non‐linear regression (MLR) model.
Calculation of Octanol/Water Partition Coefficients (logP) using Artificial Neural Networks and Connection Matrices
Authors: Schaper Klaus‐Jürgen , Samitier Maria Luisa Rosado
Published: October 2006

Artificial neural networks of the backpropagation type with three layers (input, hidden, output) are able to recognize structural molecular features determining the lipophilicity of unionized organic molecules and to directly use the chemical structure for the calculation of the partition coefficient [logP(octanol/water)]. Using a network with three neurons in the hidden layer and binary variables to indicate the presence or absence of atom types and bond types a standard deviation of s = 0.248 was obtained in the correlation between logPobs. and logPcalc. for a small training set of 268 simple organic molecules containing C, H, N, O, S, halogens. For a test set of 50 similar molecules the predicted logP values were satisfactory (s = 0.659).
Development of Methods to Ascertain the Predictivity and Consistency of SAR Models: Application to the U.S. National Toxicology Program Rodent Carcinogenicity Bioassays
Authors: Zhang Ying Ping , Sussman Nancy , Rosenkranz Herbert S. , Klopman Gilles
Published: October 2006

Models investigating relationships between chemical structures and biological activities are receiving increased recognition for the identification of chemicals with the potential for inducing adverse health effects. The relationships can be either qualitative (noted as SAR) or quantitative (noted as QSAR). The objective of the present study was to define an effective process for evaluating such models. The predictivity of SAR/QSAR models derived from the U.S. National Toxicology Program Rodent Carcinogenicity Bioassay endeavor by CASE/MultiCASE was evaluated by several different approaches: leave‐one‐out tests, 10‐fold cross‐validations and by the use of an independent test set. The goodness‐of‐fit for the data used in the model building, the predictivity for the chemicals not contained in the model, and the consistency of the predictions for a group of chemicals by different SAR/QSAR sub‐models were examined systematically. Individual prediction indices generated by CASE/MultiCASE, arbitrary combinations thereof, as well as weighted combinations using Bayes' theorem, were utilized to derive predictions of Carcinogenicity. Combinations derived using Bayes' theorem provided the most predictive model. The closeness between sub‐models based on the leave‐one‐out procedure and the full model (all chemicals used for model building) makes it the most reliable process for the estimation of a model's predictivity. However, the similarity between the predictions of the leave‐one‐out models and the 10‐fold cross‐validation models indicates that the latter process provides an acceptable approach.
Analysis of a Large Structure‐Activity Data Set Using Recursive Partitioning
Authors: Hawkins Douglas M. , Young S. Stanley , Rusinko Andrew
Published: October 2006

Conventional parametric methods such as linear regression have not been entirely successful in analyzing structure‐activity data sets. This is because the underlying relationships may involve nonlinearities, thresholds and interactions, all of which considerably impede linear additive modelling approaches. Recursive partitioning, RP, is able to accommodate all these modelling difficulties seamlessly and therefore invites investigation as a general approach for study of structure activity relationships.

In this paper we apply a recursive partitioning procedure, FIRM, to a large monoamine oxidase structure‐activity data set. The methodology is successful in uncovering nonlinearities in the response. Coupling RP with the use of correspondence analysis provides further insights into the distinction between compounds that are inactive, moderately active and active.
Studies on Propafenone‐type Modulators of Multidrug Resistance III: Variations on the Nitrogen
Authors: Chiba Peter , Hitzler Manuela , Richter Elisabeth , Huber Mario , Tmej Claudia , Giovagnoni Emiliano , Ecker Gerhard
Published: October 2006

A series of piperazine‐ and piperidine‐analogous propafenone derivatives was synthesized and tested for their ability to modulate PGP‐mediated multidrug resistance. A good correlation between lipophilicity and activity was obtained for a set of 13 compounds. Nevertheless, 4‐hydroxy‐4‐phenylpiperidines 4a–d generally showed higher activity than predicted. A QSAR equation for the complete set of compounds was obtained when using both lipophilicity and an indicator variable for compounds 4a–d (I=1; else I = 0) or H‐bond donor strength of the 4‐hydroxy group (rcv2 = 0.90; n=17). Synthesis of aniline derivatives demonstrated that the propanolamine nitrogen interacts in protonated form. Studies on a series of diphenylalkylamines indicate, that steric factors also seem to play a role for the interaction of the nitrogen with PGP.
Comparative Molecular Field Analysis (CoMFA) on [6] + [6] Fused Pyrazines with Nematocide Properties
Authors: Martínez Ana , Ochoa Carmen , Rodríguez Juan , Rodríguez Mercedes , Castro Ana , González Mercedes , Martínez María Mercedes
Published: October 2006

Quantitative structure‐activity relationship (QSAR) studies, using the Comparative Molecular Field Analysis (CoMFA), on a series of 6,7‐diarylpteridine derivatives showing nematocide properties have been carried out. The CoMFA model generated in the study has been used to estimate the namatocide activity (MIC50) of seven 6,7‐diarylpteridines related to those previously studied. The model is highly predictive for all pteridine derivatives in the test set. Moreover, this model also predicts satisfactorily the nematocide activity of other [6] + [6] fused pyrazines (quinoxalines and pyridopyrazines) which were not represented in the training set. The analysis revealed the importance of steric factors (64.8%) and then the electrostatic ones (35.8%). Most pteridines under study were previously synthesized and tested as nematocide agents. Now, the synthesis and biological evaluation of 6,7‐di‐(2′‐thienyl)‐4(3H)‐thioxo‐pteridine 36 are reported.
Enzymes In Vitro as indicators for pesticides: An examination
Authors: Wiegand‐Rosinus Maria , Wfm Ursula Obst , Haberer Klaus , Wild Aloysius
Published: October 2006

Pesticides—a serious problem especially for drinking water quality—frequently are potent inhibitors of enzymes in their target organisms. As the established chemical analyses of pesticides are time‐consuming, complicated, and expensive, so‐called screening methods are urgently needed. For this purpose the sensitivity of 13 different enzymes was tested in vitro by inhibiting their kinetic rates and/or substrate conversions by 16 pesticides (herbicides and fungicides). Because of the stabilization and resulting low sensitivity of enzymes commercially available—especially in test kits—it was necessary to vary the test conditions and to develop special methods for detecting enzymatic inhibitions. It was shown that the sensitivity to pesticides of the different enzymes varies in a wide range, partly in irrelevant high concentrations. Four enzymes seem to be suitable for inhibition tests, but need to be checked before practical application. The enzyme aldehyde dehydrogenase (AlDh), isolated from yeasts, was very sensitive to ethendithiocarbamates. Therefore an inhibition test could be developed to detect this class of pesticides in a range of some μg/L. The AlDh inhibition test is the first part of an enzymatic screening system for pesticide pollution in water. © 1992 John Wiley & sons, Inc.
MetPAD: A bioassay kit for the specific determination of heavy metal toxicity in sediments from hazardous waste sites
Authors: Bitton Gabriel , Campbell Marjorie , Koopman Ben
Published: October 2006

MetPADTM, a bioassay kit designed for the specific determination of heavy metal toxicity in environmental samples, was evaluated for toxicity assessment of sediment elutriates from hazardous waste sites in Florida. MetPAD, when run concurrently with Microtox® was useful in pinpointing sediments with heavy metal toxicity. MetPAD results were confirmed by heavy metal analysis of the samples. The MetPAD bioassay for the specific detection of the presence of bioavailable heavy metals should be included in test batteries for toxicity assessment of sediments. © 1992 John Wiley & sons, Inc.
Effects of copper and nickel on the growth of nitrosomonas europaea
Authors: Sato Chikashi , Schnoor Jerald L. , McDonald Donald B.
Published: October 2006

The toxic effects of copper(II) and nickel(II) species on the growth of Nitrosomonas europuea were investigated. The initial conditions of media were defined in terms of chemical speciation using a chemical equilibrium model. The investigation measured the response of N. europaea (the oxidation of ammonium to nitrite) cultured in a simple medium containing five cations (Ca2+, Mg2+, Fe2+, K+, Na+ ) and five inorganic ligands (CO2−3, SO2−4, Cl−, PO3−4, OH−), to changing concentrations of heavy metals (Cu2+, Ni2+) and total ammonia (NH3 plus NH+4). Experimental conditions were controlled as to allow interpretation of the results in terms of chemical species and their toxic effects on the organisms.

Decrease of the specific growth rate of N. europaea was linearly correlated (r≥ 0.90) with the logarithmic activities of Cu(II)‐ammine species (i.e., CuNH2+3, Cu(NH3)2+2, Cu(NH3)2+3, Cu(NH3)2+4,), regardless of the total copper(II) activity in the medium. Nickel(II) was far less toxic than copper(II) on the basis of specific growth rate, but nickel induced a lag or synchronized growth on the culture. The duration of lag increased with increasing total nickel concentration, while it decreased significantly as total ammonia concentration increased. The lag time was highly correlated (r>0.85) with total nickel and Ni2+ activities on log‐log scale at high ammonia concentrations, but no particular nickel species was implicated as the toxic agent. The toxicity of copper and nickel were markedly influenced by the substrate concentration.
Continuous biodegradation and detoxification of chlorinated phenols using immobilized bacteria
Authors: Portier R. J. , Fujisaki K.
Published: October 2006

Glass, cellulose and chitin materials were used as immobilized supports for porous solid matrix attachment of bacterial strains in continuous flow biocatalyst studies for chlorinated phenols detoxification. Several bacterial strains, isolated from diverse aquatic environments in south Louisiana, were utilized in continuous biotransformation and detoxification of select chlorinated phenols typically found in industrial effluents. Toxicants included phenol, 2–chlorophenol, 2,4‐dichlorophenol, 2,4,5‐trichlorophenol and pentachlorophenol. Continuous removal of 100 ppm solutions were achieved for periods of 3 months or longer. Residual levels of 100 ppb or less were noted. Mathematical models of biotransformation kinetics were tested based on laboratory results.
Application of ligating loops to control bleeding during endoscopic surgery for a highly vascular hypopharyngeal tumour
Authors: Nakahira M , Nakatani H
Published: October 2006

Endoscopic treatment of hypervascular lesions of the hypopharynx is challenging because of difficulty in controlling bleeding during surgery. We report a highly vascular hypopharyngeal solitary fibrous tumour treated by endoscopic laser surgery combined with ligating loops. Application of dual ligating loops provided easy and secure haemostasis of the feeding artery before resection. Since the endoscopic approach is less invasive than the external approach, we confirm that it is worthwhile to attempt an endoscopic approach using ligating loops before resorting to the external approach in the treatment of hypervascular hypopharyngeal lesions.
Parental satisfaction with health services provided to children with Down syndrome in north-west England: an ENT perspective
Authors: Hans P S , Belloso A , Sheehan P Z
Published: October 2006

Aims: To evaluate parents' satisfaction with medical and allied health services provided to children with Down syndrome in north-west England, comparing ENT and its allied services with other areas of health service provision.

Methods: A questionnaire survey of parents attending a north-west England Down syndrome association conference. Demographic data, departments visited, satisfaction with each service (scored one to five), waiting times for each service (scored one to five), service need (scored one to three) and accessibility (scored one to three) were recorded.

Results: Otolaryngology had been used by 50 per cent of children, with a satisfaction of 2.63 (the second worst score). Speech and language therapy was used by 90 per cent of the children, with a satisfaction of 3.26 (the worst score). The service felt to be most needed and also most difficult to access was speech and language therapy.

Conclusion: Otorhinolaryngology departments should assess how they can improve their service to this population with specific ENT needs. Speech and language services for children with Down syndrome should be expanded.
Early pulmonary response in rats infected with Trichinella spiralis
Authors: VENTURIELLO S. M. , VERZOLETTI M. L. , COSTANTINO S. N. , FORASTIERO M. A. , ROUX M. E.
Published: October 2006

The migratory stage of Trichinella spiralis, the newborn larva, travels along the pulmonary microvascular system on its way to the striated muscle cells. In the present study, an important inflammatory reaction was observed on days 5 and 14 post-infection (p.i.) in the lungs of infected rats. This inflammation was characterized by a Th2 cell phenotype of hyperplastic bronchus-associated lymphoid tissue and by goblet cell hyperplasia. Among the inflammatory cells were eosinophils and mast cells scattered over the pulmonary parenchyma. On day 5 p.i. the number of IgE+, CD4+ and CD5+ cells in the bronchus-associated lymphoid tissue were increased and IgE-secreting lung cells were also detected. At the end of the migratory phase of the infection (day 14 p.i.), only IgE+ cells were detected in high numbers and in the bronchoalveolar lavage fluid, an increment in the total IgE levels as well as the presence of IgE and IgA anti-larvae surface were also detected. In cytotoxicity assays, cells from the bronchoalveolar lavage had considerable biological activity since they were able to kill the larvae even in the absence of specific antibodies. These results show that the lung is an organ involved in the immune response developed early during a T. spiralis infection and suggest its importance in the protection of the host.
Interactions between parasites of the cockleAustrovenus stutchburyi: hitch-hikers, resident-cleaners, and habitat-facilitators
Authors: LEUNG T. L. F. , POULIN R.
Published: October 2006

The patterns of association between parasites within a particular host are determined by a number of factors. One of these factors is whether or not infection by one parasite influences the probability of acquiring other parasite species. This study investigates the pattern of association between various parasites of the New Zealand cockleAustrovenus stutchburyi. Hundreds of cockles were collected from one locality within Otago Harbour, New Zealand and examined for trematode metacercariae and other symbionts. Two interspecific associations emerged from the study. First, the presence of the myicolid copepodPseudomyicola spinosuswas positively associated with higher infection intensity by echinostomes. The side-effect of the copepod's activities within the cockle is suggested as the proximate mechanism that facilitates infection by echinostome cercariae, leading to a greater rate of accumulation of metacercariae in cockles harbouring the copepod. Second, a positive association was also found between infection intensity of the metacercariae of foot-encysting echinostomes and that of gymnophallid metacercariae. This supports earlier findings and suggests that the gymnophallid is a hitch-hiker parasite because, in addition to the pattern of positive association, it (a) shares the same transmission route as the echinostomes, and (b) unlike the echinostomes, it is not capable of increasing the host's susceptibility to avian predation. Thus, both active hitch-hiking and incidental facilitation lead to non-random infection patterns in this parasite community.