SAR and QSAR modeling of endocrine disruptors.

A number of xenobiotics by mimicking natural hormones can disrupt crucial functions in wildlife and humans. These chemicals termed endocrine disruptors are able to exert adverse effects through a variety of mechanisms. Fortunately, there is a growing interest in the study of these structurally diverse chemicals mainly through research programs based on in vitro and in vivo experimentations but also by means of SAR and QSAR models. The goal of our study was to retrieve from the literature all the papers dealing with structure-activity models on endocrine disruptor xenobiotics. A critical analysis of these models was made focusing our attention on the quality of the biological data, the significance of the molecular descriptors and the validity of the statistical tools used for deriving the models. The predictive power and domain of application of these models were also discussed.

Structural e-bioinformatics and drug design.

Nowadays the in silico scenario for drug design is totally dependent on structural biology and structural bioinformatics. A myriad of free bioinformatics applications and services have been posted on the web. This mini-review mentions web sites that are useful in structure-based drug design. The information is given in a logical manner, following the drug design process i.e. characterization of a protein target, modelling the protein using sequence homology, optimization of the protein structure and finally docking of small ligands into the active site.

Homology model of the rainbow trout estrogen receptor (rtERalpha) and docking of endocrine disrupting chemicals (EDCs).

A model for rainbow trout (Oncorhynchus mykiss) estrogen receptor (rtERa) was built by homology with the human estrogen receptor (hERa). A high level of sequence conservation between the two receptors was found with 64% and 80% of identity and similarity, respectively. Selected endocrine disrupting chemicals were docked into the ligand binding domain (LBD) of rtERa and the corresponding free binding energies Delta(DeltaG(bind)) values were calculated. A Quantitative Structure-Activity Relationship (QSAR) model between the relative binding affinity data and the Delta(DeltaG(bind)) values was derived in order to predict which further organic pollutants are likely to bind to rtERa.

e-Quantum chemistry free resources.

Among computational chemistry methods, quantum mechanics calculates geometries and electronic structures with accuracy especially for systems with electronic delocalization. The use of a multiconfigurational approach is able to treat highly degenerated states such as those occurring at the transition state in some chemical reactions. Moreover, an accurate description of potential energy surfaces can be obtained with the evaluation of the dynamic electron correlation effects by this approach. Molecular properties range from simple dipole moments, vibrational frequencies or IR intensities to frequency dependent hyperpolarizabilities. Quantum chemical calculations are thus an attractive source of molecular descriptors which can be used in QSAR/QSPR studies and which can express all electronic and geometric properties of molecules. A survey and a comparison of the performance of free e-resources for semi-empirical and ab initio calculations is provided.

e-molecular shapes and properties.

Due to recent computer technology advances, shape analysis has gained importance in all domains. In drug design and proteomics, molecular surfaces (van der Waals surface, solvent accessible surface, solvent excluded surface, polar surface area, electron density surface, separating surface, etc.), buried surfaces (gap, cleft, cavity, etc.) as well as shape properties of these surfaces, can be easily computed and visualized via the Internet. Freely available resources from the Internet for academic use, are reviewed.

WWW small molecule modeling.

Computational chemistry and molecular modeling sites have proliferated on the Internet's world wide web. This paper provides present links to some of the more most useful ones for small organic molecule modeling, and offering free resources.

Hazard identification by methods of animal-based toxicology.

This paper is one of several prepared under the project "Food Safety In Europe: Risk Assessment of Chemicals in Food and Diet" (FOSIE), a European Commission Concerted Action Programme, organised by the International Life Sciences Institute, Europe (ILSI). The aim of the FOSIE project is to review the current state of the science of risk assessment of chemicals in food and diet, by consideration of the four stages of risk assessment, that is, hazard identification, hazard characterisation, exposure assessment and risk characterisation. The contribution of animal-based methods in toxicology to hazard identification of chemicals in food and diet is discussed. The importance of first applying existing technical and chemical knowledge to the design of safety testing programs for food chemicals is emphasised. There is consideration of the presently available and commonly used toxicity testing approaches and methodologies, including acute and repeated dose toxicity, reproductive and developmental toxicity, neurotoxicity, genotoxicity, carcinogenicity, immunotoxicity and food allergy. They are considered from the perspective of whether they are appropriate for assessing food chemicals and whether they are adequate to detect currently known or anticipated hazards from food. Gaps in knowledge and future research needs are identified; research on these could lead to improvements in the methods of hazard identification for food chemicals. The potential impact of some emerging techniques and toxicological issues on hazard identification for food chemicals, such as new measurement techniques, the use of transgenic animals, assessment of hormone balance and the possibilities for conducting studies in which common human diseases have been modelled, is also considered.

Synthesis and QSAR studies in 2-(N-aryl-N-aroyl)amino-4,5-dihydrothiazole derivatives as potential antithrombotic agents.

A series of 2-(N-aryl-N-aroyl)amino-4,5-dihydrothiazole derivatives have been synthesized via cyclocondensation of N-aryl thioureas with 2-bromoethylamine hydrobromide followed by the reaction of the product thus obtained with aroyl chlorides. Title compounds were evaluated for their antithrombotic activity in vivo in mice where one of these compound 29 provided 65% protection as compared to 77% protection offered by the standard Indomethacin. Quantitative Structure-Activity Relationship (QSAR) studies were performed on these compounds using physicochemical (hydrophobic, electronic, steric) parameter as independent and antithrombic activity as dependent parameter, where antithrombotic activity correlated best (r > 0.8) with electronic parameters (F, sigma or mu) having high statistical significance > 99.9% (F(2,22)>15.0; F(2,22alpha:0.001)=11.0) suggesting that hydrophobic, steric and resonance factors are insignificant in this set of molecules for the activity.

An ab initio investigation of 2-amino-2-imidazoline: a key moiety in chemical and biochemical processes.

The 2-amino-2-imidazoline moiety is currently used not only in drugs, but also in insecticides, and fungicides. Ab initio calculations are performed to evaluate the molecular properties of the two tautomeric forms and the protonated form with extended basis sets ranging from 6-31G* to 6-311++G** at Hartree-Fock and density functional (BLYP and B3LYP) levels. Møller-Plesset perturbation is tested at the MP2/6-31G* level only. Optimized geometry structures, energies and thermochemical properties are generated. Basis set and correlation effects on geometries, tautomer equilibrium constant and protonation enthalpy are carefully analysed. Although observed for the isolated molecule, these results may be extrapolated to chemical and biochemical systems of interest.

Modelling drugs and receptors using potentials: examples in the GPCRs' domain.

Shape complementarity, electrostatic and hydrophobic matching, were used to model drugs and receptors. From known experimental data on alpha1A/alpha2A-adrenergic ligands and alpha1A/alpha2A-adrenoceptors, a model for the ligand binding sites, based on the structure of bacteriorhodopsin as a template, was proposed and built. Agonists and antagonists have overlapping but different binding sites. Emphasis was given on the role of the disulphide bridge and on the role of the sodium site. The model was extended to other G-protein coupled receptors.

Molecular characteristics of carbaryl, a CYP1A1 gene inducer.

Carbaryl belongs to a series of compounds that activate the CYP1A1 gene. This study demonstrates the inability of carbaryl to compete with 2,3,7,8-tetrachlorodibenzo-p-dioxin for binding to the rat aryl hydrocarbon (dioxin) receptor. Structural and physicochemical properties of this insecticide, in relation to the requirements for binding to the aryl hydrocarbon receptor, are described. The crystal structure was determined experimentally using X-ray diffraction. A conformational search using molecular mechanics was performed by means of a Monte-Carlo-type method and a stochastic dynamics simulation. Lipophilicity calculations, log P, and molecular lipophilicity potential are also presented. Common and discriminating properties of carbaryl and aryl hydrocarbon receptor ligands are discussed.

Effects of carbaryl and naphthalene on rat hepatic CYP1A1/2: potential binding to Ah receptor and 4S benzo(a)pyrene-binding protein.

Activation of the CYP1A1 gene has been described to be mediated by the cytosolic Ah receptor (AhR) and a possible cooperative role of the 4S benzo(a)pyrene-binding protein (4S protein). Carbaryl (CAR) has been shown to induce human CYP1A1 gene expression without binding to the human AhR. In this study, Sprague-Dawley rats received a single i.p. dose of 20, 80, 150 micromol/kg CAR or NAPn (naphthalene, the aromatic part of CAR) and were sacrificed after 24 h. CAR increased ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase activities, the level of CYP1A1, 1A2 proteins, and CYP1A1 mRNA at the highest dose, whereas NAPn showed no effects. Moreover, CAR, naphthol (its major metabolite) and NAPn were not ligands in vitro of the TCDD binding site of AhR or the benzo(a)-pyrene binding site of 4S protein in rat, neither was CAR a ligand of these two binding sites in mice, dog, monkey or human. Molecular properties of CAR were evaluated and showed that this molecule is far from the structural characteristics of CYP 1A1 specific inducers although a planar conformation can be achieved with an energy < 5 kJ x mol(-1). The data demonstrated that CAR could also modulate the AhR-mediated responses, even though it did not meet the structural requirements to be ligand of AhR.

Synthesis and evaluation of pyrazolignans. A new class of cytotoxic agents.

A series of fused pyrazole derivatives of cyclolignans have been prepared through simple chemical routes and evaluated for their cytotoxic activities in culture cells of P-388 murine leukemia, A-549 lung carcinoma and HT-29 colon carcinoma. Despite the lack of the lactone moiety in their structures, they show IC50 values at microM levels.

Synthesis of a new dipeptide template, its X-ray structure, and modeling studies on its conformational features.

The diastereoselective synthesis is reported of a dipeptide template which is closely related to H-Gly-Trp-OH. Intramolecular bond formation between alpha-C of Gly and ring position 2 of the Trp unit has been achieved by a Pictet-Spengler-type electrophilic aromatic substitution. The absolute configuration of the N-Moc protected dipeptide template 9.2H2O was determined by single-crystal X-ray crystallography and found to be (2S,5S). The cis orientation of the amino and carboxy termini prompted us to investigate the potential of 9 as a beta-turn mimic. MD calculations on the model pseudopeptide Ac-Ala-Gly-Trp-Ala-NHMe 11 suggest that an unusually tight turn should be favoured rather than a beta-turn. The proper protective situation as a pre-requisite for the incorporation of the template into a peptide has been established, and comments about its chemical properties are given.

Molecular modeling of 5-HT3 receptor antagonists: geometrical, electronic and lipophilic features of the pharmacophore and 3D-QSAR study.

If the geometrical pharmacophore of 5-HT3 receptor antagonists has been proposed by different authors, the electronic and lipophilic features of the ligands had to be precised. A 3-D QSAR study has enlightened the importance of three parameters derived from molecular electrostatic and molecular lipophilicity potentials. A multiple linear regression equation has been established. Its predictive character (non specific binding of 3[H]-ICS 205-930) has been tested with success for three different new ligands.

2-amino-2-oxazolines, VII: Influence of structural parameters on the antidepressant activity of 5-(1-aryl-4-piperazino)methyl-2-amino-2-oxazolines.

A series of 5-(1-aryl-4-piperazino)methyl-2-amino-2-oxazolines has been prepared and screened for antidepressant activity. Their lipophilic behaviour has been discussed in relation to the nature and the position of substituents on the aromatic ring. The influence of steric effects on the pharmacological activity has been investigated using experimental methods (X-ray diffraction, NMR) and theoretical calculations (semi-empirical quantum mechanics). The ortho-substitution on the phenyl ring or the C-alpha substitution on the piperazine ring by a methyl group results in the same effects i.e. an increase of the angle between the two rings up to 64 degrees (X-ray and calculation) and a loss of the antidepressant activity. Using NMR, only the influence of the ortho-substitution has been observed.

Inhibitory effect of aryl thienyl-ketones and -thioketones on arachidonic acid-induced malondialdehyde formation in human platelets: biological data and molecular modelling.

A series of anti-thrombotic aryl thienyl-ketones and -thioketones was assayed in vitro for their inhibitory effect on malondialdehyde (MDA) production induced by arachidonic acid in human platelets. For several compounds MDA formation was strongly inhibited indicating that the anti-platelet target was situated on the cyclooxygenase pathway. A comparison between the inhibition constant Ki and the IC50 values revealed competitive inhibition kinetics. The molecular structure of one active compound was analysed by X-ray diffraction and theoretical calculations to provide information on its electronic and lipophilic properties.

2-Amino-2-oxazolines, III: Synthesis, structure, and preliminary pharmacological evaluation of cycloaddition compounds with unsaturated carboxylic esters.

The reaction of 5-substituted 2-amino-2-oxazolines with unsaturated carboxylic esters yielded 2,3,5,6-tetrahydro- and 2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-7-ones. The structure of these compounds was established by IR- and NMR-spectra and by X-ray crystallography. They were tested for anti-arrhythmic and hypocholesterolemic activities.

2-Aminooxazolines, I: Crystal and molecular structure of 5-(1-aryl-4-piperazino)methyl-substituted derivatives with antidepressant activity.

The structure of two 5-(1-aryl-4-piperazino)methyl-2-aminooxazolines were determined by X-ray crystallography. An amino form is preponderant in a free base whereas an imino form is preponderant in a salt. The molecular conformations were studied by molecular mechanics.