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Biomedical subjects

J C Dearden

Publications and source records attributed to J C Dearden.

At least 19 recordsLinked to original sources
PubMed2006

Linear QSAR regression models for the prediction of bioconcentration factors by physicochemical properties and structural theoretical molecular descriptors.

The development of QSAR models useful for the prediction of fish bioconcentration factor (BCF) for a wide range of different chemical classes is crucial for the assessment and prioritisation of potentially persistent bioaccumulative and toxic substances. In this study we present QSAR models for BCF developed on a wide range of chemical structural classes of environmental and toxicological interest (such as dyes and various chlorinated and brominated compounds). The aim is to provide valid QSAR models, statistically validated for predictivity, for the prediction of BCF in general, but also for problematical chemical classes such as highly hydrophobic chemicals. Several descriptors, calculated by different commercially available software packages, have been employed in order to take into account relevant information provided by physicochemical properties (octanol/water partition coefficient and water solubility) and molecular features (structural and quantum-chemical molecular descriptors). The best descriptor subsets for the models were selected using the Genetic Algorithm-Variable Subset Selection strategy (GA-VSS) and calculations were performed by ordinary least squares regression. Starting from a data set of 640 compounds (logK(ow) range from -2.34 to 12.66), we developed linear QSARs, firstly for a data set of 620 compounds (logK(ow) range from -2.34 to 10.35) and secondly specifically for 87 highly hydrophobic chemicals (logK(ow) range from 6.00 to 10.35). All these models have been statistically validated (both internally by cross-validation and bootstrap and externally, by "a priori" splitting of available data by Kohonen Map-ANN in training and prediction sets) and their structural chemical domain has been verified by the leverage approach.

Animals↗
PubMed2005

Henry's law constant of hydrocarbons in air-water system: the cavity ovality effect on the non-electrostatic contribution term of solvation free energy.

In this study, a quantitative structure-property relationship (QSPR) model for the prediction of Henry's law constants of aliphatic hydrocarbons in air-water system has been developed, based on a data-set of 189 compounds. The well-known linear thermodynamic relation between the logarithm of Henry's law constant and solvation free energy has been used for developing the model. It is emphasised that the solvent-accessible surface area (SASA) descriptor is not adequate for predicting the solvation free energy of a wide range of aliphatic hydrocarbons; there are many compounds that have the same solvent-accessible surface area with different solvation free energy. Therefore, we have introduced cavity ovality as a good descriptor of molecular cavity shape factor. The root mean square error (RMSE) of the QSPR regression model based on SASA improves from 0.40 to 0.22 by introducing the cavity ovality descriptor. The QSPR linear ovality model has good statistical parameters (r(2) = 0.90). To emphasise the significant effect of the new descriptor, a non-linear neural network model with only two nodes in the hidden layer was developed, and also yielded a RMSE of 0.22.

Air↗
PubMed2004

QSARS for toxicity to the bacterium Sinorhizobium meliloti.

In the present study, structure-activity relationship (QSAR) models for the prediction of the toxicity to the bacterium Sinorhizobium meliloti have been developed, based on a data set of 140 compounds. The data set is highly heterogeneous both in terms of chemistry and mechanisms of toxic action. For deriving QSARs, chemicals were divided into groups according to mechanism of action and chemical structure. The QSARs derived are considered to be of moderate statistical quality. A baseline effect (relationship between the toxicity and logP), which can be related to non-polar narcosis, was observed. To explain toxicity greater than the baseline toxicity, other structural descriptors were used. The development of models for non-polar and polar narcosis had some success. It appeared that the toxicity of compounds acting by more specific mechanisms of toxic action is difficult to predict. A global QSAR was also developed, which had square of the correlation coefficient r2 = 0.53. A QSAR with reasonable statistical parameters was developed for the aliphatic compounds in the data set (r2 = 0.83). QSARs could not be obtained for the aromatic compounds as a group.

Forecasting↗
PubMed2002

Quantitative structure-permeability relationships (QSPRs) for percutaneous absorption.

Quantitative structure-permeability relationships (QSPRs) have been derived by many researchers to model the passive, diffusion-controlled, percutaneous penetration of exogenous chemicals. Most of these relationships are based on experimental data from the published literature. They indicate that molecular size (as molecular weight) and hydrophobicity (as the logarithm of the octanol-water partition coefficient; log k(ow)) are the main determinants of transdermal penetration. This article reviews the current state of the art in QSPRs for absorption of chemicals through the skin, and where this technology can be exploited in future research. The main shortfalls in QSPR models result from inconsistency and error of the experimental values used to derive them. This is probably caused by the manner in which they employ data from a variety of sources and, in some cases, slightly different experimental protocols. Further, most current models are based on data generated from either aqueous or ethanolic solution, where each penetrant is present at its saturated solubility or a fraction of its saturated solubility. No models currently account for the influences of formulation upon percutaneous penetration. Current QSPR models provide a significant tool for assessing the percutaneous penetration of chemicals. They may be important in determining the bioavailability of a range of topically applied exogenous chemicals, and in issues of dermal toxicology and risk assessment. However, their current use may be limited by their lack of applicability across different formulation types. As a consequence, their true value may be to make predictions within specific formulation types, as opposed to a general model based on a range of formulation types. In addition, the endpoint of models may be inappropriate for specific applications other than the systemic delivery of topically applied chemicals.

Administration, Cutaneous↗
PubMed2002

The components of the "critical quartet" log Kow values assessed by four commercial software packages.

Partition coefficient (log Kow) values of 103 compounds in four different solvent-water systems (alkane-water, octanol-water, chloroform-water and propylene glycol dipelargonate (PGDP)-water--the "critical quartet") were published by Leahy et al. (1992). J. Chem. Soc. Perkin Trans. 2, pp. 723-731. They used the Abraham LSER (linear solvation energy relationship) descriptors to model the log Kow values in the four systems. The calculation of Abraham LSER descriptors has now been computerized in the ABSOLV program, and we have used ABSOLV, and three other commercial software packages (HYBOT-PLUS, Molecular Modeling Pro and QsarIS) that calculate descriptors of similar classes, to model partitioning in the four solvent-water systems. Stepwise regression selected broadly similar types of descriptor from each software package to model logKow values in each solvent-water system. Overall, HYBOT-PLUS gave the best results. The rĵle of the various classes of descriptor (size, polarity, polarizability, hydrogen bonding) in modeling partitioning in the four different solvent-water systems is discussed.

Forecasting↗
PubMed2002

The importance of hydrophobicity and electrophilicity descriptors in mechanistically-based QSARs for toxicological endpoints.

Quantitative structure-activity relationship (QSAR) analysis of four toxicological data sets is described. The toxicological data include three data sets retrieved from the literature (the toxic and metabolic effects of 23 aliphatic alcohols on the perfused rat liver; the toxicity of 21 pyridines to mice; the lethality of 55 halogenated hydrocarbons to the mould Aspergillus nidulans). In addition, the toxicity of 13 mono- and di-substituted nitrobenzenes in a 15 min assay using the alga Chlorella vulgaris was analysed. QSARs were developed successfully using descriptors to describe uptake in the organism (i.e. hydrophobicity as quantified by the logarithm of the octanol-water partition coefficient, log P) and reactivity at the site of action (i.e. electrophilicity as quantified by the energy of the lowest unoccupied molecular orbital, E(LUMO)). A further parameter describing molecular branching as also required to model the data for the aliphatic alcohols. The results demonstrate that mechanistically based QSARs can be developed for these diverse endpoints which are, in terms of statistical quality as good as, if not better, than QSARs based on less mechanistically interpretable descriptors.

Animals↗
PubMed2001

Design, synthesis and biological testing of a novel series of anti-inflammatory drugs.

Many of the non-steroidal anti-inflammatory drugs (NSAIDs) currently marketed produce severe gastro-toxic side effects. The benefits of producing NSAIDs without these side effects are obvious, particularly for patients requiring long-term therapy. The aim of this investigation was to produce novel NSAIDs, based on paracetamol, that exhibit little or no gastro-toxicity. The work covers design, synthesis and testing of 13 drug candidates. The analgesic and anti-inflammatory potencies of the drug candidates were measured using the mouse abdominal constriction assay and the carrageenan-induced rat paw oedema assay, respectively. The stomachs of the rats were examined post-mortem, to assess the gastro-toxicity of the drugs. Of the 13 compounds described herein, 11 were shown to possess analgesic activity at 2-10 times the potency of aspirin, while 8 demonstrated anti-inflammatory activity at 3-10 times the potency of aspirin. Significantly, all of the compounds showed very low gastro-toxicity when compared with aspirin. The results of this study indicate that it is possible to develop novel, potent NSAIDs based on the structure of paracetamol. These compounds have the advantage of demonstrating much lower gastro-toxicity than NSAIDs currently available. Drugs of this type may, in future, provide effective treatments for inflammatory disorders.

Abdomen↗
PubMed2000

The use of atomic charges and orbital energies as hydrogen-bonding-donor parameters for QSAR studies: comparison of MNDO, AM1 and PM3 methods.

Hydrogen-bonding, important in drug-receptor interactions, also determines the solubility and partitioning of drugs between phases. It is, therefore, important to incorporate the effects of hydrogen-bonding in studies of quantitative structure-activity relationships (QSAR). In this study the atomic charge on the most positively charged hydrogen atom in a molecule and the energy of the lowest unoccupied molecular orbital (LUMO) have been used as a measure of hydrogen-bond-donor capacity. For several hydrogen-bonding acids the Mulliken atomic charges and the energy of the LUMO produced by use of three semiempirical methods, AM1, PM3 and MNDO, and MNDO electrostatic-potential-derived atomic charges, have been compared in correlations with solvatochromic hydrogen-bonding acidity (sigmaalpha(H)2). Atomic charges and LUMO energies, particularly those calculated by use of the AM1 and MNDO methods, were found to correlate well with sigmaalpha(H)2. They were also found to be good models of hydrogen-bonding in QSAR correlations.

Hydrogen Bonding↗
PubMed1999

Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships.

Permeability coefficients for 114 compounds across excised human skin in vitro were taken from Kirchner et al. Forty-seven descriptors were calculated encompassing the relevant physicochemical parameters of the compounds. Quantitative structure-permeability relationships (QSPRs) were developed using least-squares regression analysis. A two-parameter QSPR, describing the permeability coefficients (Kp) across excised skin, was obtained: log Kp=0.772 log P -0.0103 Mr - 2.33 where log P is the logarithm of the octanol-water partition coefficient and Mr is molecular mass. This equation indicates that percutaneous absorption is mediated by the hydrophobicity and the molecular size of the penetrant. Comparison with a QSPR based on penetration across a synthetic (polydimethylsiloxane) membrane suggests that the mechanisms of drug flux across polydimethylsiloxane membranes and excised human skin are significantly different.

Chemical Phenomena↗
PubMed1998

QSAR study of the toxicity of benzoic acids to Vibrio fischeri, Daphnia magna and carp.

The toxicities of benzoic acids to Vibrio fischeri, Daphnia magna and carp were measured. The results showed that the toxicity to V. fischeri and Daphnia decreased in the order of bromo > chloro > fluoro approximately equal to aminobenzoic acids. The toxicity of substituted benzoic acids to carp and Daphnia was much lower that to V. fischeri. The results also showed that the toxicity of benzoic acids to Daphnia decreased as the pH increased. It is suggested that ionized and non-ionized forms have different toxic responses. The non-ionized form may play an important role in toxicity because the toxicity of benzoic acids to Daphnia greatly decreases as the pH increases. The toxicity of benzoic acids to Daphnia may operate through non-polar narcosis, based on the regression results between the toxicities and partition coefficients (log P) and apparent partition coefficients (log D). However, toxicity cannot be predicted from non-polar baseline models because the ionized and non-ionized form of benzoic acids have different contributions to toxicity. Compared with the single descriptors, the prediction of toxicity of the benzoic acids was improved remarkably by using log P with pKa and log P with ELUMO. For the toxicity of benzoic acids to V. fischeri, it is suggested that the toxic mechanism may be different from the mechanism in Daphnia and carp. A probable reason is that V. fischeri is a unicellular organism with low lipid content, and hence both ionized and non-ionized forms of benzoic acids can easily cross the cell membrane and contribute to toxicity.

Animals↗
PubMed1998

An investigation of the mechanism of flux across polydimethylsiloxane membranes by use of quantitative structure-permeability relationships.

Quantitative structure-permeability relationships (QSPRs) based on readily calculated parameters have been developed to study penetration across a polydimethylsiloxane membrane. Maximum steady-state flux values for 256 compounds through a polydimethylsiloxane membrane were taken from previous studies. Forty-three physicochemical parameters were calculated for each compound and their significance to flux determined. Removal of fourteen outliers enabled derivation of a significant three-parameter QSPR based on the number of hydrogen-bond acceptor and donor groups and sixth-order path molecular connectivity. Models based on parameters important for penetration across human skin (log P and molecular weight) were comparatively poor. This model suggests that the mechanism of flux across a polydimethylsiloxane membrane is based mainly on hydrogen-bonding effects; as such it occurs via a mechanism of action different from that of penetration of the skin in man.

Administration, Cutaneous↗
PubMed1997

Structural basis for the haemotoxicity of dapsone: the importance of the sulphonyl group.

The structural basis of dapsone (4,4'-diaminodiphenyl sulphone) haemotoxicity has been determined by investigation of the in vitro bioactivation of a series of 4-substituted arylamines. In the presence of rat liver microsomes, dapsone (100 microM) was the most potent former of methaemoglobin in human erythrocytes (44.8 +/- 6.7%). Substitution of the sulphone group with sulphur (11.6 +/- 1.4% methaemoglobin), oxygen (4.5 +/- 1.1%), nitrogen (0.0 +/- 3.2%), carbon (13.6 +/- 0.8%) or a keto group (34.0 +/- 6.1%) resulted in a decrease in methaemoglobin formation. Only one compound, 4,4'-diaminodiphenylamine, generated significant (P < 0.001) amounts of methaemoglobin (25.6 +/- 2.5%) in the absence of NADPH. To assess further the role of the 4-substituent in methaemoglobinaemia, the toxicity of a series of 4-substituted aniline derivatives was also studied. Of the anilines studied, 4-nitroaniline caused the most methaemoglobin (36.5 +/- 8.0%), whilst aniline caused the least (0.3 +/- 0.5%). Overall, there was a significant correlation (r2 = 0.83) between the haemotoxicity and the Hammett constant, sigma(p), suggesting that it is the electron-withdrawing properties of the substituent that influence the methaemoglobin formation. In the presence of microsomes prepared from two human livers, dapsone was the most haemotoxic bis arylamine, whereas 4-iodoaniline was the most potent methaemoglobin former (60.6 and 73.6%) and aniline the least potent (1.1 and 2.4%). As a whole, these results indicate that the sulphonyl group, which is essential for the pharmacological activity of dapsone, is also largely responsible for the haemotoxicity seen with this drug.

Animals↗
PubMed1996

Descriptors and techniques for quantitative structure-biodegradability studies.

Biodegradation occurs mainly through microbial enzyme attack, and enzyme-catalysed reactions are known to depend on hydrophobic, electronic and steric effects. However, most QSBR studies involve correlation with a single parameter, but there is no consistency regarding the class of parameter. This suggests that biodegradation occurs through a range of different mechanisms. A few QSBR studies have reported the need to include more than one class of parameter in correlations. As well as linear regression analysis, other correlation methods have been used in QSBR investigations. These include discriminant analysis, neural networks and comparative molecular field analysis (CoMFA).

Bacteria↗
PubMed1996

A QSAR study of anti-inflammatory N-arylanthranilic acids.

A detailed quantitative structure-activity relationship (QSAR) analysis of a series of 112 anti-inflammatory N-arylanthranilic acids has been performed to determine which physicochemical properties of these compounds are responsible for their anti-inflammatory activity. The results indicate that activity is modelled best by molecular shape parameters. The angle between the planes of the two benzene rings, dictated by the substitution pattern of the compounds, also appears relevant to activity. Dipole moments show some significance, but log P and other physiochemical parameters correlate poorly with activity. The best QSAR obtained was: [equation: see text] where B1 and B3 are Verloop substituent width parameters and mu(bond) is bond dipole (position in parentheses).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Quantitative structure-activity relationships as a tool to assess the comparative toxicity of organic chemicals.

Quantitative structure-activity relationships of toxicity are discussed as a means of assessing the value of the Microtox test which uses the light-emitting bacterium Vibrio fisheri (Photobacterium phosphoreum) as a replacement for toxicity testing in higher species. The Microtox test is found to be a good surrogate for testing in fish, for compounds acting by the narcosis mechanism. However, for reactive chemicals the Microtox test significantly underestimates the potential hazard. It should not therefore be used in isolation for such chemicals, but rather as part of a battery of tests.

Animals↗
PubMed1995

CoMFA analysis of biodegradability.

CoMFA (comparative molecular field analysis) has been used to correlate the biodegradability of several classes of compounds. The technique uses an atomic probe to detect the steric and electrostatic fields around a molecule. Good cross-validated correlations were obtained for some series (alcohols, carboxylic acids and linear alkyl benzene sulphonates). Correlations were weaker for esters and benzene sulphonates, and were non-existent for phenols. These results may reflect the unreliability of biodegradation data, but may also be a result of molecular misalignment in the CoMFA procedure. CoMFA appears to be a potentially very useful method for the prediction of biodegradability.

Alcohols↗
PubMed1995

Quantitative structure-activity study of the toxicity of benzonitriles to the ciliate Tetrahymena pyriformis.

The toxicities of 34 benzonitriles to Tetrahymena pyriformis have been measured. Structure-activity relationships indicate that for these compounds different mechanisms of toxic action are taking place dependent on the nature of the substituent. Benzonitrile itself, some halogenated and the toluene derivatives model as non-polar narcotics; more polar substituents model well as polar narcotics; whilst the nitro and aldehyde substituted benzonitriles, and compounds that may be metabolised to benzoquinone are shown to exhibit considerable excess toxicity and, thus, the probability is that they are acting by a specific mechanism of action. After the removal of two outliers, QSAR analysis reveals a significant three parameter equation, and confirms the importance of hydrophobicity and descriptors of reactivity for the comprehension and the prediction of the toxicity of the benzonitriles.

Animals↗