bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation Analysis Between Watersolubility, Octanol‐water Partition Coefficient and Melting Point Based on Clustering
Authors: Nouwen Johan , Hansen Björn 
Published: October 2006

AbstractBy means of clustering according to structure similarity one can manage easily large databases containing several tens of thousands of chemicals. A new methodology in which statistical criteria are used to decide the optimal threshold in the clustering process is proposed. Clustering defined the several chemical classes that were present in our training set. All the clusters except one showed a correlation of logWS with logKow and melting point. The latter covers all chemicals with melting points below room temperature, resulting in a logWS‐logKow relationship. This cluster showed also a weak correlation, probably due to the insufficient number of available screens. Such a limited number of screens permits that rather different chemicals share the same cluster. Using statistical criteria, our approach resulted in 3 QSARs with reasonably good predictive capabilities. The models resulting from the smaller clusters are characterised by high correlation coefficients, describing the cluster itself very well. Due to our stringent bootstrap criterion, they perform close to random models as indicated by the statistical characteristics. Some clusters showed rather low correlations. The well behaved models proved their usefulness through external validation. The logWS‐values calculated using our QSARs agreed within 1 log‐unit with these reported in the literature.
Quantum‐chemical Descriptors for Estimating the Acute Toxicity of Electrophiles to the Fathed minnow (Pimephales promelas): An Analysis Based on Molecular Mechanisms
Authors: Karabunarliev Stoyan , Mekenyan Ovanes G. , Karcher Walter , Russom Christine L. , Bradbury Steven P. 
Published: October 2006

AbstractEstimating the toxicity of reactive xenobiotics to aquatic organisms requires physicochemical descriptors of passive transport and chemical reactions with nucleophilic biological ligands. Herein, electrophiles whose toxic action is attributed to nucleophilic substitution (SN), Michael‐type addition and Schiff‐base formation were examined. Training sets for each molecular mechanism were generated through substructure search applied to chemicals in a fathead minnow (Pimephales promelas) database. Based on a delineation of compounds by a presumed molecular mechanism, relationships between modes of toxic action, potency (96‐hour LC50 values) and mechanistically‐appropriate quantum‐chemical descriptors were explored. Monohalo‐C(sp3) function which may give rise to SN reactivity was encountered in 35 compounds. The inclusion of ELUMO, a nonspecific electrophilicity descriptor, to the generic LC50 ‐ hydrophobicity relation increased the explained variance from r2 = 36% to 69%. Eighteen potential Michael‐type acceptors, mainly acrylates, were identified by the presence of a localized CC double bond at an α, β position to a polar group. Due to different modes of action, the toxic potency of these chemicals varies almost independently of hydrophobicity (r2 = 0.12). Two additional electronic descriptors that are consistent with the likely molecular mechanism provide a multivariate QSAR with r2 = 0.78. Forty‐five aldehydes and 3 formamides comprised the training set associated with probable Schiff‐base mechanism of toxicity. The results suggest a marginal increase of toxic potency from that expected due to narcosis for more electrophilic carbonyl groups. Overall, it was concluded that regressions based on data sets that combine reactive chemicals with narcotics typically require an electronic descriptor in addition to hydrophobicity, even if the compounds all contain a common electrophilic moiety related to the putative specific reaction mechanism. However, without the generation of additional toxicity data from chemical sets that incorporate a broader range of electronic and steric character, it will likely remain extremely difficult to develop a quantitative ability to predict the potency of electrophilic compounds.
Quantum‐chemical Descriptors for Estimating the Acute Toxicity of Substituted Benzenes to the Guppy (Poecilia reticulata) and Fathead Minnow (Pimephales promelas)
Authors: Karabunarliev Stoyan , Mekenyan Ovanes G. , Karcher Walter , Russom Christine L. , Bradbury Steven P. 
Published: October 2006

AbstractBenzene derivatives elicit variable modes of toxic action to fish and, as a result, their toxic potency does not depend exclusively on bioaccumulation. In an attempt to develop quantitative structure‐activity relationships (QSARs) for acute toxicity across a relatively large and well‐defined chemical domain, a series of benzenes extracted from existing collections of toxicity data for guppies (Poecilia reticulata) and fathead minnows (Pimephales promelas) were studied. The selection of compounds was based on “prohibited” substructural screens that represent inherently reactive electrophilic groups or other chemical functions known to induce particular toxic effects. The resultant correlation samples were comprised of 64 and 122 substituted benzenes tested on the guppy and fathead minnow, respectively. The QSAR analysis showed that, for both samples, the toxicodynamic component of the toxic potency is mainly related to the electrophilicity of the aromatic ring in terms of the maximal acceptor superdelocalizability, Amax. By inclusion of Amax as an additional variable into the generic log LC50 ‐ log Kow linear regression, the explained variance increased from 51% to 73% and from 67% to 83% for the guppy and fathead minnow data sets, respectively. The significance of Amax is interpreted by the fact that it provides a crude differentiation between benzenes acting through different modes of toxic action. For the guppy sample, a significant three‐variable QSAR (R2 = 0.855) was derived, which employed both maximal acceptor and donor superdelocalizabilities as electronic descriptors and provided a more definite quantitative separation for the benzene derivatives.
3D‐modelling and Prediction by WHIM Descriptors. Part 6. Application of WHIM Descriptors in QSAR Studies
Authors: Todeschini Roberto , Gramatica Paola 
Published: October 2006

AbstractThree‐dimensional molecular indices (WHIM descriptors), proposed in Part 5 [1] are used to search for quantitative structure–activity relationships to investigate the physico‐chemical properties and biological activities of different classes of environmental important compounds.Chlorobenzenes are studied for their interesting physico‐chemical properties, e.g., melting and boiling points, solubility, lipophilicity (log Kow), bioconcentration factor (BCF), and for toxicity (Microtex test and algae). The antagonism of N,N‐dimethyl‐2‐halo‐phenethylamines to epinephrine and histamine is successfully modelled and compared with other models in the literature. Finally, good QSAR models are obtained for modelling the receptor binding affinities (RB) and inductions of aryl hydrocarbon hydroxylase (AHH) for some dioxin analogue compounds, polyhalogenated aryl derivatives.All the obtained models confirm the high modelling power of the WHIM descriptors.
Quantitative Structure‐Function Relationships of the Single‐Point Mutants of Haloalkane Dehalogenase: A Multivariate Approach
Authors: Damborský Jin 
Published: October 2006

AbstractThe applicability of multivariate statistical methods for the systematic analysis of results from the site‐directed experiments was tested. Dehalogenation data obtained with 15 single‐point mutants of haloalkane dehalogenase of Xanthobacter autotrophicus GJ10 has been related to various physico‐chemical properties of substituted amino acids. A two component model which explains 84% of activity data was derived. The most influential properties, required on position 172 in haloalkane dehalogenase were: aromaticity, main‐chain flexibility, refractivity and bulkiness, and were related mainly to the transition state/halide stabilization. The general usage of multivariate techniques for quantitative structure‐function relationships (QSFR) and protein engineering studies can be recommended. Score and loading plots from Principal Component Analysis (PCA) of physico‐chemical properties of amino acids can be used for planning and design of site‐directed mutagenesis experiments, while the models obtained from Projection to Latent Structures (PLS) can provide predictions on the effect of the mutations on protein functionality prior to its testing.
Conformational Analysis of two Inhibitors of Prolyl‐endopeptidase: Comparison of 4‐Phenyl‐butyryl‐ and Octanoyl‐prolyl‐pyrrolidine
Authors: Fehér Miklós , Kánai Károly , Podányi Benjámin , Hermecz István 
Published: October 2006

AbstractThe conformational analysis of two prolyl‐endopeptidase (PEP) inhibitors was performed. A molecular mechanics based random conformational search showed that 4‐phenyl‐butyryl‐prolyl‐pyrrolidine (1) is U‐shaped in most low‐energy conformations. The results were compared with semiempirical AM1 calculations. In contrast, the molecule octanoyl‐prolyl‐pyrrolidine (2) has a linear alkyl‐chain, although the U‐shaped conformations, required for the same mechanism of action, can be easily attained. The results of conformational analyses were compared with those of NMR measurements. The common pharmacophore for these and several other PEP inhibitors was derived.
Molecular Modelling of the Neurophysin II/Vasopressin Complex
Authors: Kaźmierkiewicz Rajmund , Czaplewski Cezary , Lammek Bernard , Ciarkowski Jerzy 
Published: October 2006

AbstractNeurophysins I and II (NPI and NPII) serve in the neurosecretory granules as carrier proteins to the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively. The (NPII/VP)2 heterotetramer, believed to be the smallest functional unit, was modelled using a low‐resolution structure information, viz. the Cα‐carbon atom coordinates of the homologous NPII/dipeptide complex (file 1BN2 in the Brookhaven Protein Data Bank) and a recently proposed (from the transfer NOE experiment) NPI‐bound OT structure as template. An all‐atom representation was obtained using standard modelling tools available within the SYBYL suite of programs (by Tripos, Inc.). The starting complex was elaborated for further refinements by two alternative strategies, termed Model I and Model II. Model I consisted of a constrained simulated annealing (CSA) protocol while Model II consisted of carefully elaborated sets of constrained minimizations. Both Models were terminated with a ∼ 100 ps molecular dynamics (MD) in water using the AMBER 4.1 force field. The free homodimer NPII2 was obtained by the removal of the two VP subunits from their sites and elaborated according to Model I only. Both models have lead to structures similar to the solid state NPII/dipeptide complex and the recently published the NPII/OT (cross)complex. Nonetheless, Model I as one implementing constrained simulated annealing and thus less amenable to personal bias, is further recommended as a method of choice for the preparation of the starting all‐atom structures for MD. The MD simulations indicated that both in the homodimer and in the heterotetramer the 310 helices display increased mobility relative to the remainder of the protein. Also, the C‐terminal domains in the (NPII/VP)2 heterotetramer are more mobile than the N‐ terminal ones. In addition to a pair of distinct inter‐monomer attractive contributions, provided by H‐bonds from Ser25 O7 of one NP unit to Glu81 Oϵ of the other, nonbonded attractive interactions involving binding site of unit 1(2) and the inter‐mononer interface of unit 2(1) are clearly seen. We speculate that both the increased mobility of the 310 helices and carboxyl domains, as well as these interactions may contribute to the allosteric communication between the ligand binding and the NPII dimerization.
On the Possible Coplanar Conformation and Dioxin‐type Toxicity of Tetrachlorobenzyltoluenes
Authors: van Haelst Anniek G. , Tromp Peter C. B. , Govers Harrie A. J. , De Voogt Pim 
Published: October 2006

AbstractSemi‐empirical molecular modelling calculations of ring rotational energy barriers were carried out for 96 tetrachlorobenzyltoluenes (TCBTs) to provide insight in the possible coplanarity of these compounds, which is required for dioxin‐type toxicity. Comparative calculations were performed for the structurally related polychlorinated biphenyls (PCBs) and polychlorinated diphenylethers (PCDEs). On account of this comparison PCBs, PCDEs and TCBTs were divided into groups of different energy barriers. PCDEs and TCBTs were classified into the same relatively high energy barrier groups. Using the criterion of fitting within a 3 × 10 Å geometry and using structure activity relationships, our results indicate that two out of the 91 coplanar TCBTs can interact with the dioxin (Ah) receptor.
A Pharmacophore Model for PDE IV Inhibitors
Authors: Polymeropoulos Emmanuel E. , Höfgen Norbert 
Published: October 2006

AbstractBased on conformational analysis and GRID‐contour calculations we developed a common primary pharmacophore for rolipram analog, nitraquazone and xanthine derivative PDE IV inhibitors. In spite of the structural differences exhibited by the three substance classes we could provide evidence that they share common hydrogen bonding and lipophilic enzyme binding sites.
Quantitative Structure‐Time‐Activity Relationships (QSTAR): pH‐Dependent Growth Inhibition of Escherichia coll by Ionizable and Nonionizable Kojic Acid Derivatives. Part II
Authors: Piršelová Katarína , Baláž Štefan , Šturdík Ernest , Ujhelyová Regina , Veverka Miroslav , Uher Michal , Brtko Július 
Published: October 2006

AbstractThe previously published model of the model‐based quantitative structure‐time‐activity relationship (QSTAR) for growth inhibitory activity of nonionizable series of kojic acid (5‐hydroxy‐2‐hydroxymethyl‐4H‐pyrane‐4‐one) derivatives against Escherichia coli has been extended for the complete set consisting of 21 nonionizable and 14 ionizable compounds. The inhibitory activity has been characterized by the isoeffective concentrations causing 50%‐decrease in the specific growth rate in comparison with the untreated control after the five exposure periods in 7 media differing in their pH values (pH 5.6–8.0). For an acceptable fit of the model to the data the receptor binding of both ionized and nonionized molecules had to be considered and the model modified accordingly. The model describes the toxicity of the tested compounds as an explicit non‐linear function of hydro‐phobicity, pKa values, the size of the substituent in the position 2, the pH values of the external media, and the time of exposure. The results can be interpreted as follows. Elimination as well as binding to the receptor have been positively influenced by both size of the molecules and ionization. The ionized molecules exhibit about 2.6 × 103 stronger binding to the receptors than their nonionized counterparts. The QSTAR model can be used for rational development of more effective derivatives.
Use of Electron Densities in Comparative Molecular Field Analysis (CoMFA): A Quantitative Structure Activity Relationship (QSAR) for Electronic Effects of Groups
Authors: Vaz Roy J. 
Published: October 2006

AbstractThe description of field‐induction σ (σi) parameters in a Comparative Molecular Field Analysis has been previously attempted by incorporating electrostatic fields computed either from point charges or from electrostatic potentials. Also, σ as well as σi have been correlated for a series of groups (–X) with the lowest electrostatic potential around the nitrogen in a series of singly substituted (NH2 – X) amines [6,7]. Here a correlation is established between both field‐induction and resonance σ (σi and σr respectively) parameters for a series of groups (–X) and electron densities of molecules (R‐X) substituted with these groups, incorporated into a Comparative Molecular Field Analysis (CoMFA). The correlation has been established for a series of singly substituted amines (R=NH2‐) as well as para substituted benzoic acids (R=HOOC(p) ‐ C6H4‐) with the correlation coefficients being explained quite well. The crossvalidated r2 (q2) as well as the predicted r2 for a different series of groups have provided valid stress tests for the correlations. The electron densities for the various substituted amines are calculated using the AMI Hamiltonian in MOPAC5 [19].
A Chemically Intuitive Molecular Index Based on the Eigenvalues of a Modified Adjacency Matrix
Authors: Burden Frank R. 
Published: October 2006

AbstractA new molecular index is proposed that is derived from the eigenvalues of a modified adjacency matrix. The construction of the matrix is chemically intuitive in that its elements relate to atomic and bonding properties. The index was tested by comparing its performance in predicting the experimental LogP of 230 compounds. The predictive power of the index is shown to be both superior than and complementary to traditional connectivity indices, χ, for LogP.
Quantitative Structure–Activity Relationship Studies on Some Nonbenzodiazepines Binding to Benzodiazepine Receptor
Authors: Paleti Anitha , Gupta S. P. 
Published: October 2006

AbstractQuantitative structure–activity relationship (QSAR) studies are made on some nonbenzodiazepine ligands of benzodiazepine receptor (BZR), namely a series of 6‐arylpyrrolo[2,1‐d][1,5]benzo‐thiazepines, a series of pyrido[1,2‐a]benzimidazoles, and a series of some fused imidazopyridines. A Fujita‐Ban approach adopted for the first series led to the suggestion that the most advantageous substituents in the series were only 4‐Cl and 7‐OCON(CH3)2. All other substituents were found to have negative contributions to the binding of the compounds with the BZR. In the case of pyrido[1,2‐a]benzimidazoles, the 8‐CONHR group was found to play an important role in the binding. The activity was found to be significantly correlated with the hydrophobic property of the R moiety and the electron‐withdrawing ability of the ortho substituents in it. In the case of imidazopyridines, the Fujita‐Ban approach revealed only the negative effects of the substituents that really mattered. By Hansch analysis these negative effects were accounted for by steric parameters.
Simple Quantum Chemical Parameters as an Alternative to the Hammett Sigma Constants in QSAR Studies
Authors: Ertl Peter 
Published: October 2006

AbstractThe Hansch‐Fujita correlation analysis proved to be one of the major breakthroughs in the process of understanding relation between molecular properties and biological activity. In this approach the Hammett σ constants are used to characterize electronic effects of substituents. Experimentally determined σ constants have, despite their numerous very successful applications in QSAR studies, also some disadvantages, most notably availability only for limited set of substituents and not very good quality for uncommon functional groups. As an alternative the use of quantum chemical parameters is possible. In this article a methodology for theoretical estimation of Hammett σ constants is described, based on correlation with semiempirical atomic charges on the simple group attached to the substituent. The agreement with experiment for 63 most common organic substituents is good (r2 = 0.89 for σmeta and 0.93 for σpara respectively, two‐parameters equation). As an example of possible application of this theory a World Wide Web‐based program for interactive calculation of electronic substituent constants is described.
Cluster‐based Design in Environmental QSAR
Authors: Eriksson Lennart , Johansson Erik , Müller Martin , Wold Svante 
Published: October 2006

AbstractIn QSAR analysis in environmental sciences adverse effects of chemicals released to the environment are modelled and predicted as a function of the chemical properties of the pollutants. Usually, the set of compounds under study contains several classes of substances, i.e., a more or less strongly clustered set. It is then needed to ensure that the selected training set comprises compounds representing all those chemical classes. Multivariate design in the principal properties of the compound classes is usually appropriate for selecting a meaningful training set. However, with clustered data, often seen in environmental chemistry and toxicology, a single multivariate design may be suboptimal. This because of the risk of ignoring small classes with few members and only selecting training set compounds from the largest classes. In this paper, a procedure for training set selection recognizing clustering is proposed. Here, when non‐selective biological or environmental responses are modelled, local multivariate designs are constructed within each cluster (class). The chosen compounds arising from the local designs are finally united in the overall training set, which thus will contain members from all clusters. Our illustration deals with a set of 66 compounds, categorized into five classes, for which the soil sorption coefficient is available. The training set selection is discussed, followed by multivariate QSAR modelling, model validation and interpretation, and predictions for the test set.
Bats as a continuing source of emerging infections in humans
Authors: Wong Samson , Lau Susanna , Woo Patrick , Yuen Kwok‐Yung 
Published: October 2006

AbstractAmongst the 60 viral species reported to be associated with bats, 59 are RNA viruses, which are potentially important in the generation of emerging and re‐emerging infections in humans. The prime examples of these are the lyssaviruses andHenipavirus. The transmission of Nipah, Hendra and perhaps SARS coronavirus and Ebola virus to humans may involve intermediate amplification hosts such as pigs, horses, civets and primates, respectively. Understanding of the natural reservoir or introductory host, the amplifying host, the epidemic centre and at‐risk human populations are crucial in the control of emerging zoonosis. The association between the bat coronaviruses and certain lyssaviruses with particular bat species implies co‐evolution between specific viruses and bat hosts. Cross‐infection between the huge number of bat species may generate new viruses which are able to jump the trans‐mammalian species barrier more efficiently. The currently known viruses that have been found in bats are reviewed and the risks of transmission to humans are highlighted. Certain families of bats including thePteropodidae, Molossidae, Phyllostomidae, andVespertilionidaeare most frequently associated with known human pathogens. A systematic survey of bats is warranted to better understand the ecology of these viruses. Copyright © 2006 John Wiley & Sons, Ltd.
Preliminary comparison of sediment extraction procedures and exchange solvents for hydrophobic compounds based on inhibition of bioluminescence
Authors: Campbell M. , Bitton G. , Koopman B. , Delfino J. J. 
Published: October 2006

AbstractTwo procedures for extracting hydrophobic contaminants from sediment samples collected from various sites in Florida were compared. The sediments, which varied in nature and degree of chemical contamination, were extracted with dichloromethane by shaking (24 h) and sonication (15 min). The dichloromethane extracts obtained were solvent exchanged into either methanol or dimethyl sulfoxide (DMSO). The efficiency of each procedure was evaluated based on the response of Photobacterium phosphoreum in the Microtox assay to the solvent extracts. The 24‐h shaking procedure produced significantly higher toxicity than the 15‐min sonication procedure for 8 of the 10 sediment samples tested. Comparisons of methanol and DMSO as exchange solvents revealed that there was generally no significant difference between these solvents in terms of toxicity.