bluuebunny/crossref_metadata_2025 huggingface dataset:
Principles of Method Selection in Partition Studies
Authors: Hersey Anne , Hill Alan P. , Hyde Richard M. , Livingstone David J.
Published: October 2006

An integrated set of experimental methods is described which allows the determination of octanol/water partition coefficients for compounds of diverse structural type having log P values in the range – 1.3 to +4.6. This set has the advantage over a single technique of extending the scope and/or efficiency of log P measurement. A series of defined procedures for selecting the most appropriate method for a particular compound is described.

The methods, which are all modifications of established techniques, are described in detail. The “Filter Chamber” technique is a quick and accurate method for log P measurement in the range ˜ −1.3 to +2.8. The “Spectrophotometric pH Profile” allows the “Filter Chamber” range to be extended to ˜ +4.6 by measurement of the extent of partitioning at pH values where the compound is partially ionised. The third technique, “Potentiometric Partition”, relies on potentiometric rather than spectrophotometric detection and hence has applications in determination of the log P of compounds with no chromophore. Each method is exemplified by measurements on simple organic molecules having known pKa and log P values.
Quantitative Structure‐Activity Relationship Studies on a New Class of Antihypertensive Agents: Derivatives of 3‐Aryl‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[4,3‐c]pyridine
Authors: Singh P. , Sharma R. C.
Published: October 2006

The quantitative structure‐activity relationship (QSAR) has been studied for the derivatives of 3‐aryl‐4,5,6,7‐tetrahydropyrazolo[4,3‐c]pyridine for their in vitro ability to displace [3H]prazosin. The physicochemical parameters, hydrophobic (π), and electronic (σ), and the structural parameter, van der Waals volume (Vw) are found to be significantly correlated with the displacement activity of these compounds.
Hydrophobicity of N‐Acetyl‐Di‐ and Tripeptide Amides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters
Authors: Akamatsu Miki , Okutani Shin‐Ichi , Nakao Kazuya , Hong Nam Joo , Fujita Toshio
Published: October 2006

The log P value of 53 N‐acetyl‐di‐ and tripeptide amides composed of amino acids having unionizable side chains was measured in a 1‐octanol/pH 7.0 aqueous buffer system. The factors governing the variations in the log P value among these protected peptides were quantitatively analyzed to formulate a correlation equation with free‐energy‐related physicochemical and substructural parameters. The log P value was governed by the sum of the hydrophobicity of side chains and the backbone as well as by the steric effects of side chain substituents on the relative solvation of the backbone CONH groups. The log P value was found to decrease by 0.6 log unit for the peptide bond, other factors being equal. For amino acids with polar side chains, the log P value was also affected by the “polar proximity factor” and/or intramolecular hydrogen bond formation in a way similar to that of zwitterionized peptides reported previously.
A new Approach to Active‐Site Binding Analysis. Inhibitors of Acetylcholinesterase
Authors: Magee Philip S.
Published: October 2006

Receptor site binding is shown to be localized in selected atoms or substructures with relatively minor contributions from the remaining molecular framework.

Related compounds can be overlayed to form a lowest common structure or hyper‐molecule that defines every possible binding site for the series. Any attempt to analyze binding data on an atom‐by‐atom basis would clearly fail if all or most of the positions were involved in the energetics. In most data sets, analysis becomes feasible when most of the variance depends on a minority of the total occupied positions. This appears to be the case in most of the sets analyzed to date, providing us with a unique opportunity. By using atomic descriptors to model lipophilicity, London forces, steric repulsion and charge interactions, the binding site can be mapped by regression analysis. Each important site of interaction and the nature of the binding force can be clearly identified. This procedure provides a statistical method based on measured data that fully complements the visual fitting of modeled drugs into defined receptor sites by computer graphics. It has enormous potential for analysis of drug, agrochemical and toxicological binding data where crystallized enzymes and fully defined sites are unknown and may long remain so.

The method is illustrated by examples drawn from acetylcholinesterase receptor site binding.
Further Comparative Studies of Fragment Weighting Schemes for Substructural Analysis
Authors: Ormerod Ann , Willet Peter , Bawden David
Published: October 2006

This paper considers the use of fragment weighting schemes for substructural analysis studies. Experiments are reported using 2‐D and 3‐D substructural descriptors with both small and large datasets for which qualitative activity data are available. The results support previous work in suggesting the potential of probabilistic models of weighting first used in studies of text retrieval.
QSAR on Substituted Salicylamides Using with Implementation of 3D MEP Descriptors
Authors: Norinder Ulf , Högberg Thomas
Published: October 2006

A QSAR analysis of the [3H]spiperone binding affinity of 25 mono‐ and disubstituted salicylamides having F, Cl, Br, Me and Et substituents in the 3‐ and 5‐positions have been done with PLS (partial least squares in latent variables) method. Besides descriptors for size and lipophilicity, a large number of theoretically derived descriptors, i.e. polarizability, charge and molecular electrostatic potential (MEP), were used. The partial charges and the 3‐D MEPs were calculated using GAUSSIAN 80 at the STO‐3G level on model compounds lacking the pyrrolidine side‐chain. The MEPs at the van der Waals distance and at a larger distance corresponding to 3.0 Å from the aromatic plane were converted to point charges centered at the heavy atoms. The main component t1 explains 71% of the observed variance in biological activity and with inclusion of two minor components t2 and t3 a total of 88% explained variance is obtained. The size, lipophilicity and electronics of the 3‐substituent are of major importance. The MEP descriptors at the 3.00 Å distance also influence the activity despite the fact that the gross behaviour of the 2‐D MEPs was highly variable with no apparent correlation with D‐2 activity. The present study does not fully support current MEP pharmacophores on closely related compounds.
Model‐based LFER parameters and QSAR of Ligand β‐Adrenoceptor Interactions II. Estimation and QSAR of Agonistic Potency and Receptor Affinity in a Series of β‐Adrenergic phenethanolamines
Authors: Dove Stefan , Franke Rainer
Published: October 2006

Based on an equilibrium model of ligand‐β‐adrenoceptor interactions and β‐adrenergic effectuation presented in a preceding paper, LFER‐related biological parameters to characterize affinity to the receptor and agonistic potency, respectively, are derived for a series of 44 phenethanolamines from measured apparent dissociation constants, KL, and intrinsic activities αACof adenylate cyclase activation. Both parameters result from a decomposition of pKLinto pKL= pKD+ log (1 + K*). Fragment regression analysis of pKLwas used for a preceding separation of the maximal contribution of agonistic interactions to apparent affinity. The log (1 + K*) scale was then estimated as logit transformation of αAC. Hansch analyses of log (1 + K*) and pKDlead to a clear separation of molecular features like substituent positions and interaction types responsible for agonistic potency and affinity, respectively. Thus, both parameters are proved to be of practical value, particularly as the resulting regression coefficients in Hansch equations are directly related to energy contributions of “basic” interaction events.
A Fragmental Code Usable for Automatic Attribution of Lipophilicity Atomic Constants
Authors: Dubost J. P. Croizet F. , Audry E. Langlois M. H.
Published: October 2006

A flow chart is described for building a fragmental code including the same information as that contained in the fragmental graph defined by Broto and Coll. A method is then computed to automatically attribute the lipophilicity fragmental constants. This very fast method may be used to establish the Molecular Lipophilicity Potential or Autocorrelation Lipophilicity Vector, and to calculate the log P of a molecule.
A QSAR Model of Teratogenesis
Authors: Gombar Vijay K. , Borgstedt Harold H. , Enslein Kurt , Hart Jeffrey B. , Blake Benjamin W.
Published: October 2006

Four related QSAR models of teratogenesis in experimental animals have been developed: one each for heteroaromatic, carboaromatic, alicyclic and acyclic compounds. The numbers of compounds in these models range from 40 (for the alicyclic model) to 144 (for the carboaromatic model). As determined by cross‐validation using the leave‐one‐out, or jackknife, technique, the accuracy of the models in discriminating between teratogens and non‐teratogens ranges from 92.4% to 96%.

A single overall assessment of experimental teratogenesis was chosen as the biological endpoint; taking into account such factors as dosage, maternal toxicity, and affected organ systems remain to be subjects of further studies.
The Antibacterial Activity of Quinolones against E. Coli: A Chemometric Study
Authors: Bonelli Daniela , Cechetti Violetta , Clementi Sergio , Cruciani Gabriele , Fravolini Arnaldo , Savino Angela F.
Published: October 2006

A chemometric approach based on multivariate calibration and design in latent variables permits one to rationalize the antibacterial activity of quinolones against gram negative bacteria, ranking the relative importance of individual structural features, and suggesting a new active structure.
Multivariate Structure‐Activity Relationships Analysis of Fungicidal and Herbicidal Thiolcarbamates Using Partial Least Squares Method
Authors: Miyashita Yoshikatsu , Ohsako Hiroyuki , Takayama Chiyozo , Sasaki Shin‐Ichi
Published: October 2006

Eighty‐three thiolcarbamates with fungicidal and herbicidal activities have been analyzed by a partial least squares (PLS) method. A three component PLS2 model based on 5 physicochemical descriptors explains 75.6% of the fungicidal and herbicidal activity data and is highly significant according to the leave‐one‐out procedure. The interpretation of structural requirements for the compounds with both more potent fungicidal and herbicidal activities is quite easy. Candidate thiolcarbamates with both fungicidal and herbicidal activities were proposed based on the PLS2 model. The PLS2 method has a great advantage that it can handle structural descriptor data X and multivariate activity data Y and get a total picture of relationships between X and Y blocks.
A Simple Model‐Based Function for Description of Non‐Linear Bioactivity‐Hydrophobicity Profiles
Authors: Baláž ŠTefan , Wiese Michael , Seydel Joachim K.
Published: October 2006

A novel description of the relationship between bioactivity and hydrophobicity, log(1/ic) = AlogP – BP+const (ic is the isoeffective concentration and P is the partition coefficient) is derived from a model for drug disposition. The function fits experimental bioactivity‐hydrophobicity profiles with a linear ascending part and a sudden drop in bioactivity after reaching the break‐point equally well as the bilinear equation and better than parabola. Due to its simplicity and fast optimization of the adjustable parameters by linear regression analysis the function is especially suitable for the use in multivariable models.
Complete Thermodynamic Description of H‐Bonding in the Framework of Multiplicative Approach
Authors: Raevsky Oleg A. , Grigor'ev Veniamin Yu. , Kireev Dmitri B. , Zefirov Nicolai S.
Published: October 2006

A complete thermodynamic description of H‐bonding for drug design is proposed. The approach is based on applicability of multiplicative principle to enthalpy (ΔH) and free energy (ΔG) of complex formation by means of Ed(Ea) and Cd(Ca) factors:

Where Ed(Ea) and Cd(Ca) characterize the proton donor (acceptor) ability of compounds. The estimation of E and C values for 163 proton donors and 195 proton acceptors was done, making it possible to predict ΔH and ΔG for 31785 reactions. The comparison of these data with experimental ones for 936 reactions was carried out:

The substituent effect on H‐bonding ability of compounds was considered. It was established that varying of substituents at active sites can alter its proton donor (acceptor) properties over a wide range of Ed(E3, cd(ca) with sufficient overlap between values of factors corresponding to different types of active sites. One could propose this approach to be applied to quantitative estimation of thermodynamic functions of H‐bonding in substrate‐receptor complexes; also for QSAR modelling, where E and C or its linear combination might be used as molecular descriptors characterizing quantitatively the relative H‐bonding ability of biologically active compounds. The second type of applications is used by the authors when modelling QSAR by means of the program package CLARAS (Classification and Recognition of Active Structures).
The Importance of Drug‐Membrane Interaction in Drug Research and Development
Authors: Seydel J. K. , Albores Velasco M. , Coats E. A. , Cordes H. P. , Kunz B. , Wiese M.
Published: October 2006

The importance of the interaction of drug molecules with membranes is discussed. The first two examples use the interaction of benzylpyrimidines with membranes of sensitive and resistant E. coli. This leads to a partial inactivation due to binding and to a change in mechanism of action, respectively. Another example deals with the interaction of amphiphilic benzylamines with artificial bilayers which lead to a change in conformation. The neuroleptic activity of Flupirtin derivatives could be described by the degree of interaction with bilayers quantified by NMR technique and a newly developed HPLC technique. Finally the interaction of amphiphilic drugs with membranes, possibly responsible for reversal of multidrug resistance in tumor and malaria therapy, is discussed.
Dipolarity and Partition Coefficient of Solvents, Drugs and Chemicals+
Authors: Lien Eric J. , Gao Hua , Wang Fengzhen , Shinouda Hakim G.
Published: October 2006

The parameters sometimes used to describe relative polarity of the solvents are dielectric constant (e) and partition coefficient (log P). Both of them have their limitations in terms of assessing relative solubilities of various organic/inorganic compounds in solvents commonly used. In an attempt to rectify this problem, we propose to use a new term “relative dipolarity (Dr)” which is defined as Dr = μ · M/L, and a two‐dimensional Log P‐Dr plot to classify all solvents from nonpolar to polar. We have found that among the single parameters examined Dr is the best single parameter to assess the relative polarity of the commonly used solvents. Dr also correlates better (than μ or e) with Log P. We have analyzed the relationship between Log P values of 25 solvents and their physicochemical parameters including molecular weight (MW), maximum hydrogen‐bond ability (HBm), and either Dr, μ or e. The Log Poct/w values of 110 disubstituted benzenes are also very well correlated with parameters including MW, μ (or μ1 and μ2 of the substituent group dipole moments), HBm (or HBa as hydrogen‐bond acceptor and HBd as hydrogen‐bond donor).
3D‐Quantitative Structure‐Activity Relationships: Describing Hydrophobic Interactions Directly from 3D Structures Using a Comparative Molecular Field Analysis (CoMFA) Approach
Authors: Kim Ki Hwan
Published: October 2006

A method of describing hydrophobic interactions directly from 3D structures in 3D Quantitative structure‐activity relationships (QSAR) has been investigated. Molecular fields calculated with a H2O probe and the GRID force field using a comparative molecular field analysis (CoMFA) approach yield excellent correlations with significant cross‐validation. The results indicate that the CoMFA approach of describing hydrophobic interactions using a H2O probe is an excellent methodology for describing the corresponding effects in 3D QSAR studies.
A Principal Component and Cluster Significance Analysis of the Antiparasitic Potency of Praziquantel and some Analogues
Authors: Ordorica M. A. V. , Velázquez M. L. M. , Ordorica J. G. V. , Escobar J. L. V. , Lehmann P. A. F.
Published: October 2006

The cestocidal and schistocidal activities of praziquantel and 13 analogues were studied by using principal component and cluster significance analysis, together with potential function classification techniques. It was found that calculated size related properties and dipole moment significantly grouped the more active compounds, indicating their importance for activity. These results are compatible with the existence of a recognition site which mediates their antiparasitic activity and whose cavity surface must be almost exactly complementary to the pharmacophoric surface of praziquantel.
QSAR of Fungicidal Δ3‐1,2,4‐Thiadiazolines. Reactivity‐Activity Correlation of SH‐Inhibitors
Authors: Nakayama Akira , Hagiwara Kenji , Hashimoto Sho , Shimoda Susumu
Published: October 2006

Structure‐activity relationships of fungicidal Δ3−1,2,4‐thiadiazolines were investigated by using molecular orbital (MO) calculations. Semiempirical MO calculations by MNDO‐PM3 method suggested that the reactivity of HOMO at the sulfur atom in the thiadiazoline ring is important to inhibit SH‐enzymes. In order to quantify the reactivity of the thiadiazolines, we defined an index, R(1), which is the electron density of HOMO at the sulfur divided by the orbital energy of HOMO. The fungicidal activity against cucumber downy mildew highly correlated with the R(1) index and hydrophobicity of molecule. The significance of R(1) and its square term in the QSAR equations suggested that a suitable range of reactivity is required to control the plant disease through the inhibition of SH‐enzymes.
A QSAR Approach for Estimating the Aquatic Toxicity of Soft Electrophiles [QSAR for Soft Electrophiles]
Authors: Veith Gilman D. , Mekenyan Ovanes G.
Published: October 2006

This work demonstrated that descriptors of soft electrophilicity for aromatic chemicals such as average superdelocalizability and LUMO energy could be used together with the hydrophobicity descriptor, log P, to explain the variation of acute toxicity of substituted benzenes, phenols, and anilines to fish. The hydrophobicity and soft electrophilicity descriptors were shown to be orthogonal for the 114 chemicals studied. For proelectrophiles, the structure‐toxicity relationships accurately predict toxicity when the stereoelectronic parameters were computed for the metabolic activation products. The QSAR for acute toxicity using these molecular descriptors defines a toxicity plane which includes several modes of toxic action.

Type (I) narcotics are chemicals located in the region of low reactivity where toxicity varies with hydrophobicity alone. Type (II) narcotics are more toxic than type (I) narcotics at similar values of log P, and the increase can be explained by stronger electronic interactions with cellular soft nucleophiles. Highly reactive soft electrophiles which have dissociating protons such as 2,4,‐dinitrophenol produce symptoms of respiratory uncouplers. Those without dissociating protons produce symptoms of reactive toxicity consistent with covalent binding.
QSAR and Molecular Modelling for a Series of Isomeric X‐Sulfanilamido‐1‐phenylpyrazoles
Authors: Koch A. , Seydel J. K. , Gasco A. , Tironi C. , Fruttero R.
Published: October 2006

The influence of large substituents in o‐, m‐ and p‐positions of the phenyl ring of isomeric 3‐, 4‐ and 5‐sulfanilamido‐1‐phenylpyrazoles on their inhibitory effect against E.coli derived dihydropteroic acid synthase and whole cell E.coli has been studied. According to their pKa values, the 3‐ and 5‐series show high antibacterial activity while the 4‐series displays feeble inhibitory activity. In the 3‐series the variation in MIC is explained by differences in pKa (Hammett σ) and molecular weight (MW) or substituent surface respectively, whereas in the 5‐series steric effects of substituents in the o‐position of the 1‐phenyl ring and MW describe the differences in whole cell activity. In the cell‐free system the inhibitory activity depends for the 3‐series solely on pKa or Hammett σ, respectively, and in the 5‐series, where the derivatives are almost completely ionized, the variation is solely explainable by the steric effect of the substituents in o‐position. The steric effect of o‐substituents in the 5‐series has been studied and explained by NMR‐ and molecular modelling techniques. The observed differences in electronic effects of substituents comparing the 3‐ and 4‐series with the 5‐series could be explained by the results of quantum chemical calculations.
A Non‐aqueous Partitioning System for Predicting the Oral Absorption Potential of Peptides
Authors: Paterson D. Andrew , Conradi Robert A. , Hilgers Allen R. , Vidmar Thomas J. , Burton Philip S.
Published: October 2006

In the search for a better model of the rate limiting processes in peptide transport we studied the partitioning of solutes between heptane and ethylene glycol. Methods for determining the log partition coefficient (logPH/G) in this solvent system were developed and the reproducibility and ruggedness of such determinations were assessed. The partition coefficients in this system were found to correlate (r2 = 0.86, n = 11) with the permeability coefficients for a group of model peptides. To understand the physical forces governing this partitioning process, the influence of four solvatochromic parameters: hydrogen bond donor strength (α) hydrogen bond acceptor strength (β), polarity (π*), and molecular volume (V1), was evaluated for a set of 20 benzene derivatives. Multiple regression analysis revealed that the solute hydrogen bonding parameters, especially α, were the most important determinants. Molecular volume of the solute was about half as influential compared with partitioning systems in which water is the polar phase. These results suggest that the requirement for hydrogen bond breaking is the principal deterrent to peptide transport and that log PH/G is useful in predicting permeance.
A Classification Model for Allergic Contact Dermatitis
Authors: Magee Philip S. , Hostynek Jurij J. , Maibach Howard I.
Published: October 2006

A classification model based on 36 compounds inducing allergic contact dermatitis and 36 non‐allergens was developed by the discriminant technique of two‐value multiple regression analysis. One outlier was observed and several of the compounds fell in the indeterminate region between the classes. Based on variable results of clinical data (human and animal), some overlap in the model was considered more reasonable than perfect separation. The descriptors in this model clearly imply intercellular transport (LogP derived) and various forms of binding (London forces [MR] and hydrogen‐bonding [HBA, HBD]) as part of the allergic contact dermatitis (ACD) response mechanism. In addition, substructure descriptors related to the epidermal reactivity of the ACD inducers were statistically important. These include directly reactive functional groups from haptens and metabolizable precursor groups of prohaptens.

The model was developed from carefully selected compounds of diverse structure, representing a broad range of hapten and prohapten substructures without undue molecular complexity. Validation of the model is in progress on a broad range of molecular structures far beyond those used in construction.
The Use of Procrustes Analysis to Compare Different Property Sets for the Characterization of a Diverse Set of Compounds
Authors: Rose Valerie S. , Rahr Elizabeth , Hudson Brian D.
Published: October 2006

Procrustes analysis has been used to compare the similarity of 14 different sets of property descriptors for characterizing a diverse set of pharmaceutical compounds. The analysis generated 3 distinct clusters from the property sets, which could be generally described as a) mostly 2D physicochemical properties, b) physicochemical properties based on overlaid 3D molecular structures, c) connectivity indices. Compound clustering and selection methods based on similarity measures calculated from a property set in one cluster would therefore give quite different results to those from a set in a different cluster.
Study of the Effects of Basic Di‐ and Tri‐phenyl Derivatives on Malignant Cell Proliferation: An Example of the Application of Correspondence Factor Analysis to Structure‐Activity Relationships (SAR)
Authors: Gilbert Jacques , Doré Jean‐Christophe , Bignon Eric , Pons Michel , Ojasoo Tiiu
Published: October 2006

The descriptive multivariate method known as Correspondence Factor Analysis (CFA) was used to establish correlations between the structures of three chemical classes of compounds (triphenyl‐acrylonitriles (TPEs), diphenylethylenes (DPEs), and diphenylalkyls) substituted in the para position by either hydroxy or basic groups and their responses in a battery of three biochemical tests, namely the induction of the proliferation of the MCF7 human breast cancer cell‐line, the estrogen‐irreversible inhibition of MCF7 cell proliferation (herein denoted cytotoxicity), and binding to the estrogen receptor (ER). The power of CFA was illustrated by performing several analyses: (a) Construction of factorial maps that described only the specificity of the response of the TPE population in the tests or both the specificity and amplitude of the response; (b) Use of the factorial maps as mathematical models for the introduction of new variables. These variables were either further biochemical tests (cytotoxicity under different conditions, inhibition of the activation of protein kinase C) on which the TPE population had been screened or further compounds (DPEs and diphenylalkyls). Relationships among the different tests were thus assessed as well as affiliations of the new compounds with TPEs. The analyses revealed the importance of the presence and configuration of hydroxy groups in ER binding and cell proliferation, but also the ability of non‐hydroxylated compounds to induce cell growth independently of their relative affinity for ER. Cytotoxicity could be related to the presence of basic groups but also to resonance of conjugated bis‐para‐hydroxy diphenyl derivatives. Overall, the analyses stressed the complexity of the relationships between growth‐promoting and growth‐inhibitory potential of the test‐compound populations and suggested the involvement of multiple mechanisms of action.
Dynamic QSAR: A New Search for Active Conformations and Significant Stereoelectronic Indices
Authors: Mekenyan Ovanes G. , Ivanov Julian M. , Veith Gilman D. , Bradbury Steven P.
Published: October 2006

A new approach called “dynamic” QSAR is introduced to enhance the exploration of active chemicals and relevant molecular descriptors. In contrast to conventional QSAR methods where chemical structure is described by a single, low energy conformer, “dynamic” QSAR simulates the multiplicity of 3‐D molecular shapes that a molecule can assume in complex reaction environments. The core of the new methodology is the coupling of the 3DGEN algorithm which exhaustively generates conformers and a rule‐based system to rapidly screen conformers for desired properties. Hypotheses regarding receptor shape and interaction mechanisms are conveniently incorporated into the screening algorithm. A full array of Stereoelectronic parameters available to OASIS can be combined with conventional topological and physicochemical indices for all conformations and explored using a variety of mathematical and visualization techniques. The “dynamic” QSAR method is illustrated by modeling the acute toxicity of a series of unsaturated alcohols in fish.
Subcellular Pharmacokinetics and Drug Properties: Numerical Simulations in Multicompartment Systems
Authors: Baláž Štefan
Published: October 2006

The methodology and results of numerical simulations of drug distribution in multicompartment systems, represented by a catenary set of alternating aqueous and lipid compartments, are reviewed. Transport, membrane accumulation, protein binding, first order elimination (biotransformation or excretion), but not ionisation have been considered as the processes determining the drug distribution. The simulations provide the time courses of the drug concentrations in individual compartments as dependent on hydrophobicity and elimination rate parameters of drugs because the model parameters are substituted by their relationships to the drug properties. The simulation results are fitted with empirical functions, mostly in the form of the hydrophobicity‐concentration profiles for a pre‐defined time of exposure. The shape of the profiles is different for open and closed biological systems (with and without elimination, respectively) as well as for individual periods of the drug distribution in closed systems (non‐equilibrium, mixed, equilibrium). Fitting the empirical functions to experimental data enables one to verify quantitatively the simulation results. The use of the approach for formulation of mechanistic conclusions is exemplified.
The QSAR Discriminant‐Regression Model
Authors: Raevsky Oleg , Sapegin Alexei , Zefirov Nikolai
Published: October 2006

The DIscriminant‐REgression Model (DIREM) belongs to the ordinary discrete‐continuous QSAR approach, and has been proposed to explore SAR's for compounds with the same type of activity but different features of biological action. As a function scaling method, DIREM reveals the correspondence between structure descriptions and the distribution of compounds on a scale of biological activity. Model building is an iterative process that includes cluster formation using a stepwise procedure of linear discriminant analysis (LDA), and the discovery of quantitative relationships within each cluster by means of stepwise multiple regression analysis (MRA). DIREM is available in the software packages CLARAS (CLAssification and Recognition of Active Structure) and DNESTR (Design of New Effective STRuctures). Examples of DIREM application (guppy toxicity of aliphatic compounds, and β‐adrenergic activities of phenethylamines) are discussed.
QSAR in Toxicology. 1. Prediction of Aquatic Toxicity
Authors: Cronin Mark T. D. , Dearden John C.
Published: October 2006

A critical review is given of quantitative and qualitative structure‐activity relationships (QSAR) for the prediction of some acute aquatic toxicological endpoints. Consideration is given to sources of biological data and, as in all areas of toxicology, there is concern over the validity, quality and quantity of toxicological data to model. Despite these problems it is now possible to predict the acute aquatic toxicity of unreactive chemicals to many species with considerable accuracy. Predictions for other mechanisms of toxic action become less accurate as more specific toxicities are investigated. Surprisingly little work has been performed on the prediction of toxicity of inorganic elements and their complexes, to both aquatic species and other organisms.
A CoMFA Analysis of Selected Physical Properties of Amino Acids in Water
Authors: Steinmetz Wayne E.
Published: October 2006

The CoMFA methodology was applied successfully to the analysis of logD, the logarithm of the octanol‐water distribution coefficient, of free amino acids and their amino acetylated, carboxy amidated derivatives. A learning set of 38 molecules and a test set of 9 molecules was used. ‐logS, the negative logarithm of the solubility in water, was also examined with a learning set of 19 amino acids. In each case the best results were obtained with the backbone of the residues on an extended conformation and the NCαCβCγ dihedral angle set to −60.0°. A combination of fields was used in the calculations: the default Tripos steric and electrostatic fields with the default probe, a sp3 carbon atom with a + 1 charge, and a GRID field with a water probe. The GRID field which measures hydrogen bonding makes the sole contribution to the optimal model for logD. This result is consistent with the importance of the hydrophobic effect. An electrostatic field is also required in the model for ‐logS. The inclusion of the electrostatic term may reflect the contribution to ‐logS made by crystal‐packing forces.
3D‐Quantitative Structure‐Activity Relationships for Hydrophobic Interactions: Comparative Molecular Field Analysis (CoMFA) including Molecular Lipophilicity Potentials as Applied to the Glycine Conjugation of Aromatic as well as Aliphatic Carboxylic Acids
Authors: Masuda Takashi , Nakamura Katsuhiko , Jikihara Takahiro , Kasuya Fumiyo , Igarashi Kazuo , Fukui Miyoshi , Takagi Tatsuya , Fujiwara Hideaki
Published: October 2006

Hydrophobic interactions sometimes play an important role in enzymatic reactions. In order to interpret such reaction data on the basis of comparative molecular field analysis (CoMFA) some method of introducing lipophilic parameters is necessary, since in the conventional CoMFA approach only electrostatic and steric fields are included in the original version. In the present study, the idea of Molecular Lipophilicity Potential (MLP) was introduced into the original CoMFA algorithm and the glycine conjugation reactions were analyzed. The conjugation data used were the whole reaction of glycine conjugation as well as the initial step of the reaction where substrates bind to coenzyme CoA. The substrates used include aromatic as well as aliphatic carboxylic acids. The CoMFA approach can explain data of aromatic and aliphatic carboxylic acids with a single model, whereas the multiple linear regression (MLR) analysis affords separated results for these two kinds of carboxylic acids. Thus, wide applicability of the CoMFA approach is supported and the aromatic and aliphatic carboxylic acids are suggested to behave in a common fashion in the conjugation reaction of the first process.
New Analgesics Designed by Molecular Topology
Authors: García‐Domenech R. , García‐March F. J. , Soler R. M. , Galvez J. , Antón‐Fos G. M. , De Julián‐Ortiz J. V.
Published: October 2006

Molecular topology has been applied to the design of new analgesic drugs, utilizing linear discriminant analysis and connectivity functions using different topological descriptors. Of a total of 26 compounds selected, 17 showed analgesic activity. The following stood out particularly, showing analgesic values greater than 75% regarding ASA (acetylsalicylic acid), the reference drug: 2‐(1‐propenyl)phenol, 2′4′ dimethylacetophenone, p‐chlorobenzohydrazide, 1‐(p‐chlorophenyl) propanol and 4‐benzoyl‐3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one. The usefulness of the design method has been demonstrated in the search of new chemical structures having analgesic effects, some of which could become “lead drugs”.
An on‐line handwritten mathematical equation recognition system that can process matrix expressions by referring to the relative positions of matrix elements
Authors: Toyozumi Kenichi , Suzuki Takahiro , Mori Kensaku , Suenaga Yasuhito
Published: October 2006

In this paper we describe a method for performing recognition of matrix expressions in an on‐line handwritten mathematical equation recognition system. This system incrementally performs recognition of numerical expressions and text input as handwriting and outputs the recognition results as LATEX source code. In previous work we developed the functionality of the system to make it capable of recognizing other two‐dimensional structures including subscripts, square root symbols, summation notation, and fractions, but we had not previously been able to deal with matrix structures. We believe that a specialized recognition system is necessary for dealing with matrix structures because they are not expressed using any declarative symbols and involve numerical elements positioned vertically on the page. In this paper we add matrix expression recognition functionality that can be used in real time to the system; this implementation makes use of both geometric features and the relative positions of numerical elements. We performed recognition experiments using the expanded system with input containing matrix expressions and confirmed the effectiveness of the proposed method. © 2006 Wiley Periodicals, Inc. Syst Comp Jpn, 37(14): 87–96, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.10684
Adaptive understanding of proposal‐requesting expressions for conversational information retrieval system
Authors: Hosokawa Kenichiro , Fujie Shinya , Kobayashi Tetsunori
Published: October 2006

This paper considers a conversational system in which information is provided in accordance with the conditions presented by the user, and proposes a method that can adequately deal even with unknown expressions. In most conventional systems, the relation between the expression and the intention of the utterance by the user is built into the system beforehand. Thus, it is difficult to deal adequately with unknown expressions which have not been learned. We propose a framework which adaptively manages on‐line the relation between the expression and the intention by interaction with the user. The proposed method produces a framework in which the connection between the expression and the intention is dynamically modified according to the explicitness or implicitness of the affirmative or negative attitude shown by the user to the proposal made by the system. It is verified by an evaluation experiment that the system can adequately learn the relation between the expression and the intention of the user by the proposed method, and can deal adequately with unknown expressions. © 2006 Wiley Periodicals, Inc. Syst Comp Jpn, 37(14): 62–72, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.20514
A distributed algorithm for constructing minimum delay spanning trees under bandwidth constraints on overlay networks
Authors: Baduge Thilmee M. , Hiromori Akihito , Yamaguchi Hirozumi , Higashino Teruo
Published: October 2006

In this paper, we propose a new protocol that constructs a spanning tree on an overlay network given by a complete graph, in a decentralized manner. This algorithm consists of two decentralized operations, which support joining of and leaving of the overlay network at any time in the session (though there are some constraints). Whenever a node joins or leaves, the rest of the nodes (or node itself in case of join) can be repositioned (or positioned) to minimize the maximum delay from a certain set of nodes in the current tree without violating the degree constraint at each node, by applying these operations. We have confirmed the usefulness of this algorithm by performing simulation and real‐world experiments. © 2006 Wiley Periodicals, Inc. Syst Comp Jpn, 37(14): 15–24, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.20655
Development of face‐to‐face communication function for a humanoid robot
Authors: Shiomi Masahiro , Kanda Takayuki , Miralles Nicolas , Miyashita Takahiro , Fasel Ian , Movellan Javier , Ishiguro Hiroshi
Published: October 2006

In this paper the authors report on the creation of a face tracking function that combines foveal vision and peripheral vision for communications between a humanoid robot and a person. In the authors' approach, by combining foveal vision and peripheral vision using a particle filter, a function for robust face tracking and attention direction can be achieved. In particular, the authors used peripheral vision when the robot was looking at an object other than a human being in order to make a deliberate gesture, and were able to achieve robust face tracking at all times by combining foveal vision and peripheral vision when the robot was paying attention to the person's face. Moreover, robust face tracking can also be applied to conventional technologies for facial expression recognition and utterance detection during interactive communication. © 2006 Wiley Periodicals, Inc. Syst Comp Jpn, 37(14): 1–14, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.20680
Optical microarray biosensing techniques
Authors: Bally Marta , Halter Martin , Vörös Janos , Grandin H. Michelle
Published: October 2006

Microarrays provide a powerful analytical tool for the simultaneous analyses of thousands of parameters, be they DNA or proteins, in a single experiment. However, a number of challenges continue to hinder the widespread application of microarray assays for analytical and diagnostic purposes. Advances in detection methods can help overcome some of these challenges by improving sensitivity and reliability in signal detection and by enabling real‐time detection of binding events. Thus, the aim of this review is to highlight the most promising optical microarray biosensing techniques. The principles of techniques making use of labels, including scanner type, total internal reflection type, fiber‐optics‐based, and SPR‐enhanced fluorescence, are described, along with a brief summary of labeling strategies. State of the art label‐free techniques, including imaging SPR and imaging ellipsometry, are also reviewed. Examples of microarray‐based assays using each technique are given to illustrate both their usefulness and their limits of detection. Furthermore, the most competitive commercial microarray systems are presented and compared with one another in the context of their detection system. Finally, a discussion of the remaining challenges as well as trends and future applications of microarrays are presented in the context of optical sensing. Copyright © 2006 John Wiley & Sons, Ltd.
C60, Buckminsterfullerene: its impact on biological ToF‐SIMS analysis
Authors: Fletcher John S. , Lockyer Nicholas P. , Vickerman John C.
Published: October 2006

The desire to apply the analytical abilities of the time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS) experiment to increasingly diverse samples, particularly those of a biological nature, has provided the impetus for development of new technologies to overcome some of the inherent difficulties associated with such studies. Of these, one of the most important is the widespread introduction of polyatomic ion beams to increase the secondary ion yields of the higher mass, more chemically characteristic species. The introduction of the C60 ion beam for routine analysis has made arguably the greatest impact, providing new possibilities for analysing molecular compounds present both on the surface and in some cases in the bulk of samples such as biological tissue sections and single cells. Copyright © 2006 John Wiley & Sons, Ltd.
Applications of XPS in bioengineering
Authors: McArthur Sally L.
Published: October 2006

XPS has been used extensively to characterise the surface chemistry of materials used in bioengineering. Its ability to characterise both the elemental and chemical structure of the surface makes it particularly useful, as it can be used to identify the chemical functional groups present on the surface of virtually any material. This review is intended to profile both traditional applications of XPS in bioengineering as well as highlight areas where the incorporation of XPS may be able to give insight into biointerfacial interactions. Copyright © 2006 John Wiley & Sons, Ltd.
Evidence of genotoxic substances in the Niagara river watershed
Authors: Lan Que , Dickman Mike , Alvarez Mar
Published: October 2006

The SOS chromotest was used to detect genotoxicity of sediment samples from seven locations in the Welland River, Ontario, Canada, in December 1986 and April 1987. DMSO extracts of sediment samples from one location situated directly below the discharge pipe of a polyvinyl chloride plant showed a statistically significant (p < 0.01) genotoxic effect. It was concluded that genotoxic contaminants were associated with vinyl chloride contaminated sediments from this location.

At a distance of 5 m downstream of the polyvinyl chloride plant's discharge, the mean SOS induction factor was 2.05, while 100 m further downstream the SOS induction factor had dropped to 1.54.

The Ames test was used to detect genotoxicity of samples that gave positive responses in the SOS chromotest. The results of the Ames test were negative. This may suggest that the SOS chromotest is more sensitive than the Ames test for testing genotoxicity in these types of samples.
Dehydrogenase activity of soil microflora: Significance in ecotoxicological tests
Authors: Rossel D. , Tarradellas J.
Published: October 2006

The dehydrogenase activity (DHA) of the microflora of a gleyic luvisol artificially contaminated by 1, 10, and 100 μg tributylin (TBT)/g dry wt soil was compared with its ATP content, long‐term CO2 evolution, and esterase activity. DHA was measured by reduction of triphenyltetrazolium chloride. This 203‐day laboratory experiment comprised a phase of air drying, a remoistening, and the addition of a substrate (alfalfa and yeast extract). The half‐life of TBT ranged from 40 (10 and 100 μg/g) up to 70 days (1 μg/g).

The microflora was not affected by 1 and 10 μg TBT/g. After an initial 60% stimulation, the respiration and esterase activity in the soil contaminated by 100 μg TBT/g recovered to the level of the control soil in 2 and 14 days, respectively. About 50% depression of DHA and ATP content was observed throughout the 203 days of the experiment. DHA inhibition was correlated with depression of ATP content (r = 0.82). Air drying, remoistening, and substrate addition had little influence on the depression of DHA and of the ATP content.

Unlike long‐term CO2 evolution, DHA did not reflect the total effective activity of soil microflora; rather, it reflected its total potential activity. As for biomass estimates using substrate‐induced respiration, a clear distinction should be made between short‐term DHA and other measurements of DHA. Short‐term DHA, as a substrate‐induced maximum initial activity, appears mainly to reflect the biomass of soil microflora. The measurement of DHA appears to be a suitable low‐cost and sensitive tool for assessing side effects of chemicals.
Microbiotests in aquatic ecotoxicology: Characteristics, utility, and prospects
Authors: Blaise Christian
Published: October 2006

Small‐scale biological tests (microbiotests) have steadily increased in development and application over the last 30 years in the field of aquatic ecotoxicology. Multitrophic level assessment requirements, attractive features of microbiotests, and the constant search for simplicity and cost efficiency of testing are reasons explaining the expanding use of microbiotests. In this article, the major characteristics that advantageously confer popularity on microbiotests are presented and 25 currently applied aquatic toxicity microbiotests are listed. Conducted with bacteria, protozoans, microalgae, small invertebrates, and fish cell lines, these microbiotests represent a realistic cross section of those that are now becoming an essential part of ecotoxicological assessment. Microbiotests can be profitably employed for ranking and screening chemicals, for novel applications enabling rapid detection of ecotoxic effects in complex liquid samples, and for increasing the cost efficiency and diagnostic potential of hazard assessment schemes. Microbiotesting research, development, and applications will continue to surge in the 1990s, driven, among other factors, by the imperative need for cost effectiveness in environmental programs. Research in the fields of ecotoxicology, biotechnology, and immunochemistry should provide interesting breakthroughs to further enhance the specificity and diagnostic value of microbiotests.