bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of Octanol/Water Partition Coefficients of Certain Organophosphorus Compounds Using High‐Performance Liquid Chromatography
Authors: Krikorian S. Edward , Chorn Trevor A. , King James W.
Published: October 2006

Octanol/water partition coefficients (log P) for a series of dialkyl alkylphosphonates, dialkyl alkylphosphonothionates, and an alkyl alkylphosphinate have been estimated using reversed‐phase high‐performance liquid chromatography. The test compounds proved to be readily amenable to the chromatographic procedures employed, although the more lipophilic compounds appeared to be more tolerant to variations in the chromatographic conditions and methods of data handling than were the less lipophilic compounds with regard to the precision and accuracy of the log P values obtained from the retention data. The methodology was validated by carrying out shake‐flask experiments with two of the test samples. The rank order of log P values obtained was reasonably predictable, based on the sizes of the alkyl substituents present. The enhancement of lipophilic character attributable to replacement of oxygen by sulfur in the PO group is also evident from the results. The data for the phosphonates permit the calculation of a value for the hydrophobic fragmental constant for the OPO2 group (f = −2.79).
Design of a New Substituted 2,4‐Diamino‐5‐benzylpyrimidine as Inhibitor of Bacterial Dihydrofolate Reductase Assisted by Molecular Graphics
Authors: Czaplinsky Karl‐H. , Kansy Manfred , Seydel Joachim K. , Haller Rolf
Published: October 2006

A new highly active inhibitor of bacterial DHFR has been developed supported by computer graphics. The new benzylpyrimidine is especially active against mycobacteria due to its favourable properties with respect to cell wall permeation.
A Pharmacophore Hypothesis for Antidepressant Activity
Authors: Andrews Peter R. , Craik David J. , Munro Sharon L.
Published: October 2006

Previous studies of conformation‐activity relationships of antidepressant drugs are extended by considering not only more antidepressant structures, but also modelling the positions of key receptor groups. This is achieved using the program HAYSTACK to search all possible conformations of both the highly flexible tricyclic antidepressants such as imipramine and amitriptyline, and more conformationally constrained atypical antidepressants such as nomifensine and mianserin. For each compound the set of possible conformations is filtered using both energetic and distance‐geometry criteria until finally those conformations which combine lowest energy with best fit to a general receptor model are obtained. It is shown that all 12 tricyclic and atypical antidepressants considered may act at a single receptor.
Conformational Analysis of Flexible Antidepressant Drugs
Authors: Munro Sharon L. , Craik David J. , Andrews Peter R.
Published: October 2006

A complete conformational analysis is reported for the two highly flexible antidepressant drugs imipramine and amitriptyline. In both cases, all sidechain torsion angles and conformational variables associated with the tricyclic ring systems were varied in a step‐wise manner using simple molecular mechanics calculations. The results of these studies provided an overview of the mobility of both molecules. The molecular mechanics data also provided the basis for more detailed molecular orbital calculations which were used to optimize specific low‐energy conformations and conformational transitions. The results are presented using a variety of graphical techniques, including a five‐dimensional SUPERMAP which simultaneously depicts four conformational variables and the molecular energy. Both imipramine and amitriptyline are shown to be extremely flexible molecules, with the calculated barriers to conformational transitions being generally consistent with those observed using NMR spectroscopy.
An Extended QSAR Analysis of Some 4‐Aminodiphenylsulfone Antibacterial Agents Using Molecular Modeling and LFE‐Relationships
Authors: Hopfinger A. J. , De Compadre Rosa L. Lopez , Koehler M. G. , Emery S. , Seydel J. K.
Published: October 2006

The QSAR between free‐space, intramolecular conformational entropy, S, and inhibition potency, pC, of dihydropteroate synthase from dapsone sensitive M. lufu bacterial strains [1] was extended from 36 to 53 substituted 4‐aminodiphenylsulfones. In addition, S was used to establish QSARs for dihydropteroate synthase pC values from dapsone resistant M. lufu and both sensitive and resistant M. smegmatis bacterial strains. The resulting QSARs suggest there are no discernible specificity factors among the dihydropteroate synthases from the four strains. Environmental effects on S were evaluated by computing and comparing intramolecular conformational entropies in both free‐space and an aqueous medium. Overall, the aqueous solvation effects increase the intramolecular entropies by making substituents more flexible. However, a very significant correlation persists between the solvent‐dependent S and pC even though the QSAR is not as meaningful as that found for free‐space S.
Quantitative Structure‐Activity Relationships in a Set of Local Anesthetic Agents
Authors: Recanatini Maurizio , Valenti Piero , Re Paolo Da
Published: October 2006

A QSAR analysis has been carried out on a set of local anesthetic drugs structurally related to lidocaine. The surface and the infiltration activities and the acute toxicity have been examined, and their dependence upon structural as well as physico‐chemical parameters has been expressed in terms of both linear and non‐linear models. The results embodied in the correlation equations are discussed at the light of recent theories on the local anesthetic action. In accord with these theories, the hydro‐/lipophilic balance of the molecules has a basic role in modulating the potency of the compounds, also if this property can be “hidden” behind some structural features. Once the contributions of these structural characteristics have been ruled out (by means of indicator variables), the dependence of the biological response on the distribution coefficient can be quantitatively assessed.
Quantitative Structure‐Activity Relationships in Insecticidal Pyrethroid Ethers
Authors: Winkler David A. , Holan George , Johnson Wynona M. P. , Virgona Chris T. F. , Jarvis Karen E.
Published: October 2006

A series of twenty‐six insecticidal pyrethroid ethers were subjected to multiple regression QSAR analysis. The results indicated that candidate insecticides should have a lipophilicity, as expressed in the log of the calculated octanol/water partition coefficient, of approximately 5.5. There was a general, negative correlation of activity with molar refractivity, suggesting that molecular size, or volume, and polarizability should not be too large for optimum insecticidal activity.

The substituents on the aromatic ring adjacent to the cyclopropyl moiety appear to exert their primary influence via electronic effects. For optimum activity strongly electron donating para substituents are required. Electron‐withdrawing or donating effects, size and lipophilicity of the substituents on the cyclopropyl ring appear to influence the insecticidal activity. Substituents which are small, not very polarizable, not very lipid soluble and which have a positive polar electronic substituent constant are likely to be the most effective. This is consistent with the hypothesis of the pyrethroids and other toxins acting at specific receptors adjacent to ion channels embedded in nerve membranes, causing partial blockade of these sodium, or other ion, channels.

There were very few changes made to the substituents on the other aromatic ring. The results indicated that electron withdrawing groups were favoured as substituents on that ring.
Structure‐Activity Relationships for Unsaturated Dialdehydes 2. A PLS Correlation of Theoretical Descriptors for Six Compounds with Mutagenic Activity in the Ames Salmonella Assay
Authors: Nilsson Lena M. , Carter Robert E. , Sterner Olov , Liljefors Tommy
Published: October 2006

A QSAR model has been developed for the quantitative prediction of mutagenic activity in a class of unsaturated dialdehydes. The conformers of each dialdehyde were obtained from molecular mechanics (MM) calculations. The MM results were used to extract descriptors to represent the three‐dimensional structure of each compound. Thirty‐one theoretical descriptors (e.g. from MM and CNDO calculations) were correlated with the mutagenic activities of six unsaturated dialdehydes in three strains in the Ames Salmonella assay. The method of partial least squares in latent variables, PLS, was chosen for the multivariate statistical analysis. The activity of a seventh dialdehyde was predicted from this model, in encouragingly good agreement with experiment. The set of compounds is admittedly a small one, but as an initial investigation the results show the potential of this approach to QSAR modeling.
Multivariate Parametrization of 55 Coded and Non‐Coded Amino Acids
Authors: Jonsson Jörgen , Eriksson Lennart , Hellberg Sven , Sjöström Michael , Wold Svante
Published: October 2006

The previously derived z‐scales for the 20 coded amino acids have been extended to cover non‐coded amino acids. In total, 55 amino acids (35 non‐coded) were multivariately characterized by seven TLC variables, three NMR variables and two theoretical variables, resulting in three extended z‐scales (z1′, z2′ and z3′). These scales were validated in QSAR studies on two different series of peptides. They were used to model 40 bradykinin potentiating pentapeptides, and 48 dipeptides with bitter taste. The former series contained 10 peptides with non‐coded amino acids. Thus, the extended z‐scales were validated both for their coded and non‐coded parts.
High Performance Liquid Chromatographic Methods and Procedures of Hydrophobicity Determination
Authors: Kaliszan Roman
Published: October 2006

New methods and procedures of hydrophobicity determination employing high performance liquid chromatography are reviewed. After a brief analysis of the state of the art regarding the earlier developed methods, the approaches reported since 1986 are described. Advantages and limitations are discussed of the following HPLC stationary phase materials: poly (styrene‐divinylbenzene) copolymers, alkyl‐derivatized polymers, polymers immobilized on alumina and silanol‐deactivated silica‐based reversed‐phase materials. Separate paragraph is devoted to centrifugal partition chromatography (CPC) as a method of hydrophobicity determination. The new methods and materials reduce (at least partially) the limitations of alkyl‐bonded silica phases, i.e., instability at pH above 8 and specific activity of free silanol groups of the support. At the same time the new HPLC systems are of a wider hydrophobicity measuring range and are more easy to handle than the 1‐octanol‐like systems. Several of the methods proposed seem to be convenient, reliable and to yield hydrophobicity data otherwise not readily available. Providing that appropriate columns are commercially distributed the new methods may replace soon the established HPLC procedures in an average QSAR laboratory.
Correlation Analysis and Molecular Modeling of Cholecystokinin Inhibitors
Authors: Coats Eugene A. , Knittel James J.
Published: October 2006

Quantitative structure‐activity relationships for a series of N‐(R‐benzoyl)‐glutamic acid α‐alkylamides as cholecystokinin inhibitors have been elucidated. The relationships clearly define a hydrophobic binding pocket on the receptor which accomodates the alkylamides. A second hydrophobic binding region appears to interact with the benzoyl substituents. Computer graphic modeling suggests that these hydrophobic binding regions correspond to Met31 and Trp30 amino acid residues of the peptide agonist. A comparative analysis of potential carboxylate binding via GRID provides a quantitative assessment of similarities and differences between the glutamate inhibitors and the peptide agonist.
Comparison of Chemometric Models for QSAR
Authors: Cruciani Gabriele , Baroni Massimo , Bonelli Daniela , Clementi Sergio , Ebert Cynthia , Skagerberg Bert
Published: October 2006

Chemometric methods suitable for QSAR modelling, namely partial least squares (PLS) and multiple regression analysis (MRA), are compared in terms of their prediction abilities by means of the appropriate statistical parameter called standard deviation of errors of predictions (SDEP). The results show the reliability of the PLS approach and point out the risk of overfitting with MRA, which may give rise to unreliable predictions.
Multivariate Techniques for Parameter Selection and Data Analysis Exemplified by a Study of Pyrethroid Neurotoxicity
Authors: Ford Martyn G. , Livingstone D. J.
Published: October 2006

A large number of molecular descriptors (70) were calculated for a series of pyrethroid insecticides using the techniques of computational chemistry. Because the set of descriptors contains considerable redundancy, it is necessary to reduce the size of the data matrix while retaining useful information. Various techniques are available for investigation and reduction of large data sets. Several of these methods have been employed and the results of the different strategies compared. It is concluded that there is no preferred method but that each technique has advantages to offer and is complementary.
Determination of Topological Equivalence in Molecular Graphs from the Topological State
Authors: Hall Lowell H. , Kier Lemont B.
Published: October 2006

A method for computer perception of topological equivalence is presented along with consequences for analysis of molecular graphs and applications to SAR. This method is based on a new concept called the topological state of skeletal atoms. Topological equivalence is the molecular characteristic associated with structure equivalences within the molecular skeleton without regard to full three‐dimensional geometry. In this investigation, structure is represented by the chemical graph (hydrogen‐suppressed graph). Topological equivalence, the equivalence of skeletal atoms, is based upon numerical equality of the topological state values introduced in this method. The topological state value for an atom is defined in terms of three quantities: the number of skeletal paths terminating on that atom, the number of atoms in each path (graph separation), and a numerical expression for the chemical identity of each atom. Atom identity is encoded by the molecular connectivity valence delta value. Several algorithms for computation of topological state value are examined, all based on use of the geometric mean of the valence delta values of the atoms in each path. It is shown for a large number of molecules with a wide variety of structure types that proper topological equivalence perception is achieved by this method for several algorithm formulations. This formalism of topological state may prove highly useful as a characterization of the environment of skeletal atoms. The total topological index also introduced here appears to be a highly discriminating index of molecular graphs. Implications for structure‐activity studies are discussed and two example QSAR uses of the total topological index are presented: gas chromatographic retention index for alcohols and inhibition of T. mentagrohpytes by phenylpropylethers.
“Classical” and “Magnetic” Aromaticities as new Descriptors for Heteroaromatics in QSARs. PLS Prediction of Tetrahymena Pyriformis Growth Inhibition by Heteroaromatics
Authors: Ebert Cynthia , Katritzky Alan R. , Musumarra Giuseppe
Published: October 2006

The concentrations of heteroaromatics which inhibit growth of “Tetrahymena pyriformis” are tested for correlation with twelve measures of aromaticity for these compounds together with log P and the molecular connectivity. A two principal component (PC) model accounts for 65% of the total variance and demonstrates the significance of scales of magnetic aromaticity in general and of χM in particular, of log P and of molecular connectivity. PLS treatment using the three descriptors I′x, χM and log P explains 89% of the variance: a single parameter correlation with χM is almost as successful.

The potential for the present method to predict toxicities of heterocycles is indicated.
A Differential Molecular Connectivity Index
Authors: Kier Lemont B. , Hall Lowell H.
Published: October 2006

A differential molecular connectivity index, ΔmX, has been defined which is the difference between the simple and the valence connectivity indexes of the same order, m, is ΔmX = mX — mXv. The information contained in this index is largely electronic with contributions from adjacent alkyl fragments amounting to the size of m. The electronic information is a quantitation of the pi and lone pair electrons on that part of the fragment defined by m. The index is capable of modeling selected physical properties which are regiospecific within a molecule. Examples include NMR chemical shifts, gas phase basicities, ionization potentials and chromatographic retention indexes.
QSAR in Bradykinin Antagonists. Inhibition of the Bradykinin induced Contraction of the Isolated Rat Uterus and Guinea Pig Ileum
Authors: De Castro L. Felipe Pineda , Reißmann Siegmund
Published: October 2006

Quantitative structure‐activity relationships (QSAR) in bradykinin antagonists with activity on rat uterus and/or guinea pig ileum were investigated by the Free‐Wilson method in the Fujita‐Ban approach. The substituent contributions to antagonist activity were calculated by multiple linear regression. The used QSAR model adequately describes the experimental data, so that the assumption about additivity and independence of the substituent contributions to the overall activity is valid. The obtained results allow a survey of the effect of different modifications on the antagonist potency. Information about the influence of various substitutions on the selectivity of the antagonists can be extracted from the comparison of the QSAR for both the tissues studied.
Quantitative Structure‐Activity Relationships in the Prediction of Penicillin Immunotoxicity
Authors: Bartlett Alison , Dearden John C. , Sibley Peter R.
Published: October 2006

Penicillin antibiotics are one of the most important classes of pharmaceutical agents, both therapeutically and economically, in modern day usage. However a major clinical drawback is the incidence of immunologically mediated adverse reactions exhibited by the general population in response to their use.

Using the techniques of classical QSAR we have produced statistically and predictively valid models which relate

the incidence of cutaneous rash induced by oral penicillins to the similarity in shape to benzyl penicillin (n = 14, r = 0.907).

the incidence of all subjective clinical adverse reactions induced by parenteral penicillins to the ClogP and Sterimol B2 parameters (n = 12, r = 0.940).

the incidence of gastro‐intestinal disruption induced by parenteral penicillins to the number of methyl groups in the acyl side chain substituent (n = 11, r = 0.882).
A Quantitative Structure‐Activity Relationship Study on Some Cholecystokinin Antagonists
Authors: Gupta Satya P. , Mulchandani Veena , Das Subharanjan , Subbiah Arun , Reddy D Narsimha , Sinha Jyoti
Published: October 2006

A quantitative structure‐activity relationship (QSAR) study is made on three different series of cholecystokinin (CCK) antagonists, namely a series of 3‐(3‐indolylmethyl)‐1, 4‐benzodiazepines, a series of glutamic acid analogues, and a series of indole derivatives of quinazolinone. An analysis of this study leads to suggest that CCK antagonists primarily bind with the receptor through hydrogen bonds and/or hydrophobic interactions, and that this binding is further strengthened by the involvement of certain substituents in some secondary bindings through, most likely, dispersion interactions.
A CoMFA Model of Steric and Electronic Effects of Phosphorus Ligands
Authors: Steinmetz Wayne E.
Published: October 2006

The method of comparative molecular field analysis (CoMFA) has been applied to a series of 6 reactions involving a transition‐metal center and a series of substituted phosphine ligands. A CoMFA analysis of parameters used in classical QSAR including the Tolman cone angle and Brown's steric parameter ER has also been performed. Provided that the dataset of compounds is carefully chosen and is sufficiently large, CoMFA can be used in place of traditional QSAR methods which have employed Tolman cone angles and carbon‐13 chemical shifts as parameters. The CoMFA results show that steric and electronic factors have comparable weight in determining chemical reactivity in the types of reactions considered.
Using Artificial Neural Networks to Predict Biological Activity from Simple Molecular Structural Considerations
Authors: Burden Frank R.
Published: October 2006

Some simple molecular structural considerations relating to atom type were used as the independent variable inputs to an artificial neural network with the dependent variables consisting of the physicochemical parameters molecular refractivity and hydrophobicity. The low root mean squared error in each case was sufficiently low for the further mapping of biological activity to be attempted. A set of 236 dihydrofolate reductase inhibitors, for which the biological activity was known, was fitted in a similar manner and again producing a low root mean squared error. It is concluded that neural networks can be used to predict biological activity, within a series of closely related molecules, from molecular structural considerations alone so saving much effort in synthesis and in vivo testing with new candidate molecules.
Quantitative Structure ‐ Activity Relationship Studies on Benzodiazepine Receptor Binding of Some Nonbenzodiazepine Series of Ligands
Authors: Gupta S. P. , Paleti Anitha
Published: October 2006

Quantitative structure ‐ activity relationship (QSAR) studies have been performed on some non‐benzodiazepine series of benzodiazepine receptor (BZR) ligands, namely a series of thienylpyrazologuinolines and a series of imidazoquinoxalines. Studies reveal the merits and demerits of the substituents and their physicochemical properties in each case, in addition to the essential requirements for the binding for each type of ligand.
Correlation Analysis Between Watersolubility, Octanol‐water Partition Coefficient and Melting Point Based on Clustering
Authors: Nouwen Johan , Hansen Björn
Published: October 2006

By 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

Estimating 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

Benzene 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

Three‐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

The 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

The 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

Neurophysins 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

Semi‐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

Based 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

The 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

The 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

A 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

Quantitative 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

The 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

In 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

Amongst 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

Two 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.
Distinction between heavy metal and organic toxicity using EDTA chelation and microbial assays
Authors: Mazidji C. N. , Koopman B. , Bitton G. , Neita D.
Published: October 2006

Use of the EDTA chelation test in conjunction with microbioassays for general toxicity (Microtox) and heavy metal toxicity (β‐galactosidase activity) allowed us to identify the presence of heavy metal toxicity, and to distinguish between cases in which toxicity was due solely to either heavy metals, organic compounds, or a mixture of these chemicals. The technique is effective over a wide range of water hardness and pH. Screening of industrial wastewater samples by the EDTA‐microbioassay technique gave results that were consistent with chemical analysis of samples by atomic absorption. © 1992 John Wiley & sons, Inc.
Microbial degradation of polycyclic aromatic hydrocarbons and polycyclic aromatic nitrogen heterocyclics
Authors: Liu D. , Maguire R. J. , Pacepavicius G. J. , Nagy E.
Published: October 2006

Fermentor studies were conducted to examine the microbial degradation of polycyclic aromatic hydrocarbons (PAHs; naphthalene, phenanthrene, anthracene) and a polycyclic aromatic nitrogen heterocyclic (quinoline) using a mixed bacterial culture capable of utilizing these compounds as the sole carbon and energy source for growth. Half‐lives for the three PAHs in the cyclone fermentor system ranged from 1 day for naphthalene to 4 days for anthracene. Several major metabolites during the biodegradation of PAHs were also identified. These included 2‐hydroxybenzoic acid and 1‐naphthalenol (for naphthalene); 1‐phenanthrenol and 1‐hydroxy‐2‐naphthalenecarboxylic acid (for phenanthrene); and 3‐hydroxy‐2‐naphthalenecarboxylic acid (for anthracene). Thus our bacterial culture biodegraded the three PAHs by initial hydroxylation of the molecule followed by the eventual cleavage of the ring to yield the ortho‐ or meta‐cleavage intermediates, which would be further metabolized via conventional metabolic pathways. However, biodegradation of the nitrogen‐containing polycyclic aromatic hydrocarbon compound quinoline by our culture resulted in the accumulation of 4–5 metabolites, one of which has been identified as 2‐quinolinol. Work is in progress to identify the other metabolites from quinoline degradation. © 1992 John Wiley & sons, Inc.